TW201623265A - Anti-viral compounds, pharmaceutical compositions, and methods of use thereof - Google Patents

Abstract

Disclosed herein are compounds, pharmaceutical compositions, and related methods for the treatment of viral infection, including RNA viral infection in subjects. The compounds, pharmaceutical compositions, and methods can modulate the innate immune antiviral response in vertebrate cells, including activating the RIG-I pathway.

Description

Antiviral compound, pharmaceutical composition and method of use thereof

Disclosed herein are compounds, pharmaceutical compositions, and methods useful for treating viral infections (including RNA viral infections) in an individual.

As a group, RNA viruses represent a huge public health problem in the United States and around the world. Well known RNA viruses include influenza viruses (including poultry and pig isolates; also referred to herein as influenza), hepatitis C virus (HCV), dengue virus (DNV), and West Nile virus (West Nile). Virus, WNV), SARS coronavirus (SARS), MERS coronavirus (MERS), respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV). These viruses have caused pandemic outbreaks and public health threats throughout history. Flavivirus, Henipavirus, Filovirus, and Arenavirus are especially emerging RNA viruses that pose significant public health and biodefense threats. These viruses collectively put millions of people around the world at risk of infection. Many emerging RNA viruses cause hemorrhagic fever of the virus and can cause significant morbidity and mortality. Dengue virus (DNV) and West Nile virus (WNV), the flavivirus (positive-strand RNA virus), are also Arbovirus, which is transmitted by mosquitoes; therefore, these viruses are easy to use. A potential underlying biological threat that spreads in insects or animals and humans, is highly infectious, and its potential to be weaponized in bioterrorism events.

At least four subtypes of Ebola virus (EV) are contagious to humans (Zaire, Sudan, Bundibugyo, and Cote d'Ivoire). It has been stated that EVs have erupted in Africa and the mortality rate is as high as 90%. Feldmann, H. et al. (2011) Lancet 49, 1-14. Recently, other countries (including the United States) have reported cases of EV infection. The natural host of EV is not defined, but non-human primates (NHP) are susceptible to infection. The negative-strand RNA virus of the EV line Filoviridae and can be effectively transmitted from person to person.

Seasonal flu infects 5% to 20% of the population each year, resulting in 200,000 hospitalizations and 36,000 deaths. Influenza can cause young and old people or those with weakened immune systems to fall into the virus or secondary bacterial pneumonia. Coronaviruses are more common worldwide and often cause mild to moderate respiratory disease, but some coronaviruses can cause severe respiratory illness and death. In 2003, SARS-coronavirus infections in many countries caused approximately 8,000 infections and nearly 800 deaths. Recently, cases of Middle Eastern respiratory syndrome caused by MERS-Coronavirus have been reported.

More than 170 million people worldwide are infected with HCV, and 130 million of them are chronic carriers of the risk of developing chronic liver disease (cirrhosis, cancer and liver failure). Therefore, HCV is the cause of all liver transplantation in two-thirds of developed countries. Recent studies have shown that the mortality rate of HCV infection is increasing due to the increasing age of patients with chronic infection.

DNV is the most popular flavivirus in humans and is endemic in most tropical and subtropical countries and is currently occurring elsewhere (including the United States and throughout the Pacific Islands). DNV is circulating as four serotypes (DNV1-4) and after the first infection, reinfection can lead to fatal hemorrhagic fever and shock syndrome. Infections are believed to provide lifelong immunity against reinfection caused by the same serotype, but are not resistant to other serotypes. Epidemics have been reported in many countries throughout Latin America, South-East Asia and Western Pacific Regions. It is estimated that there are between 50 million and 100 million cases of dengue fever each year worldwide. Dengue hemorrhagic fever and dengue shock syndrome The group represents a serious form of the disease. Currently, there is no specific antiviral therapy for the treatment of DNV infection in the industry and there is no approved vaccine.

WNV is a local-associated flavivirus in Africa and Asia, but is now appearing in the Western Hemisphere. WNV is neuroinvasive and can cause severe encephalitis and is lethal in about 6% of cases. Neuroinvasive WNV can manifest as meningitis, encephalitis, or less frequent palsy (called polio). There was almost no WNV in North America before 1999, but it reappeared on the mainland after the outbreak of encephalitis in New York. In the following seven years, WNV infections spread throughout the United States, and current estimates indicate that as many as 2 million to 3 million Americans have been infected. In the past 20 years, outbreaks have been reported in parts of Europe, North Africa, the Middle East and North America. Currently, there is no specific antiviral therapy for WNV infection in the industry and there is no approved vaccine.

Of the listed RNA viruses, very few vaccines are currently approved for clinical use. There is a vaccine against influenza virus that must be corrected and administered annually. Therefore, drug therapy is necessary to alleviate the significant morbidity and mortality associated with such viruses. Unfortunately, the number of antiviral drugs is limited, many are less effective, and almost all are plagued by the rapid evolution of viral resistance and limited spectrum of action. Ribavirin, a guanine nucleoside analog, has been studied in a variety of clinical trials of RNA viral infection and is probably the most widely available antiviral agent. Ribavirin has been approved for the treatment of hepatitis C virus (HCV) and respiratory syncytial virus (RSV) infections, and shows that Lassa virus-related mortality is reduced by intravenous ribavirin therapy. However, as a single agent it is less effective and has significant hematological toxicity. Two types of acute influenza antiviral agents, adamantane and neuraminidase inhibitors, are only effective within 48 hours of infection, thereby limiting the window of therapeutic opportunity. High resistance to adamantane has limited its use, and the large reserve of neuraminidase inhibitors will eventually lead to the emergence of overuse and influenza resistant strains.

Based on the foregoing, there is a huge and unsatisfied effective treatment against viral infections in the industry. Demand. Most drug development efforts target viral target viral proteins. RNA viruses have small genomes, and many encode less than 12 proteins, resulting in extremely limited numbers of viral targets for novel drugs. This is the reason why the current drug has a narrow spectrum of action and most of the virus resistance. However, it is useful to discover new viral targets that can be inhibited. Alternatively, direct acting antiviral therapy can act to counteract any infection mechanism (eg, the virus enters the host cell).

Novel antiviral therapies can act directly on the virus. In particular, novel antiviral therapies can take advantage of the fact that such viruses are readily controlled by innate intracellular immune defenses that suppress viral replication and transmission. Compounds that act on cellular targets may be more effective, less susceptible to viral resistance, cause fewer side effects, and are effective against a range of different viruses. Effective spectral antiviral agents, whether used alone or in combination with other therapies, are of great benefit to current clinical practice. Although interferon is in principle host-mediated and broad-spectrum, many viruses have evolved the ability to disrupt downstream of interferon signaling by drugs acting on receptors. Important guidelines are the development of drugs that activate innate immune signaling under specific viral strategies and are uniquely complementary to conventional antiviral compounds in development or on the market. As a congenital immune antiviral response, the RIG-I-like receptor (RLR) pathway with innate antiviral immunity can strongly block RNA viral infection by the action of various antiviral defense genes.

The compounds, pharmaceutical compositions and methods disclosed herein divert the focus of viral drug development away from targeting viral proteins to innate antiviral immune responses that target and enhance the host. The present invention relates to compounds for the treatment of viral infections, including RNA viral infections, pharmaceutical compositions comprising such compounds, and related methods of use. In certain embodiments, the compounds modulate the RIG-I pathway.

Embodiments of the invention may provide compounds represented by the formula

Wherein L is NR ² , O, S, C(=O)N, CR ² R ³ CR ² R ³ , CR ² R ³ NR ² , CR ⁴ =CR ⁴ , CR ² R ³ O, CR ² R ³ S NR ² CR ² R ³ , NR ² C(=O), NS(O) _t , OCR ² R ³ , SCR ² R ³ ; V system (CR ² R ³ ) _u , C(=O)CR ² R ³ , CR ² R ³ O, CR ² R ³ OCR ² R ³ , CR ⁴ =CR ⁴ , C≡C, C(=NR ² ) or C(=O); Q series NR ² , O, S(O ) _t or a bond; t = 0,1,2; u = 0-3 ; wherein the dotted line indicates the presence or absence of the bond; R ¹ lines R ^a, oR ² or NR ² R ^3; each R ^a is independently-based H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² and R ³ are each independently R ^a , C(=O)R ^a , SO ₂ R ^a Or R ² and R ³ form an optionally substituted carbocyclic, heterocarbocyclic, aryl or heteroaryl ring; each R ^{4 is} independently R ² , OR ^a , C(=O)R ^a , C (=O)NR ² R ³ , NR ² R ³ , NR ^b (=O)R ^a , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , SO ₂ NR ² R ³ , NCOR ^a , halogen , trihalomethyl, CN, S = O, a nitro group, or two R ⁴ groups optionally form of substituted carbocyclic, heteroaryl carbocyclic, aryl or heteroaryl ring; W is and X are each independently Department of ^{N, NR a, NR 5,} O, S, CR 2 R 4 or CR ^4; R ⁵ based ^{R a, C (= O)} R a, SO 2 R a or absent; Y ^1, Y ^2, Y ³ and Y ⁴ are each independently CR ⁴ or N; and NR ² R ³ may form an optionally substituted heterocyclic or heteroaryl ring including pyrrolidine, hexahydropyridine, morpholine and hexahydropyrazine.

In some embodiments, the compound can be represented by the following formula

Wherein R ⁴ is R ^d , SO ₂ R ^d , C(=O)R ^d , NH C(=O)R ^d , R ^e , OR ^c or CF ₃ , wherein R ^c is H or C ₁ -C ₁₀ hydrocarbyl And R ^d is an unsubstituted heterocyclic ring or an unsubstituted carbocyclic ring, and R ^e is a substituted heteroaryl group or a substituted phenyl group; and n is 1 or 2.

Some embodiments of the invention may include a pharmaceutical composition comprising any of the compounds as set forth herein.

Additionally, embodiments of the invention can include a method of treating a viral infection in an individual, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition as described herein, thereby treating the viral infection in the individual.

Furthermore, embodiments of the methods of the invention may comprise administering any of the pharmaceutical compositions described herein as an adjuvant to a prophylactic or therapeutic vaccine.

Embodiments of the invention include methods of modulating an innate immune response in a eukaryotic cell comprising administering to the cell any of the compounds as set forth herein. In some embodiments, the cell line is in vivo. In other embodiments, the cell line is in vitro.

Figures 1A-1D show in vitro biological activity. In Figure 1A, it is reported by displaying IFNβ-luciferase (IFNβ-LUC, left), ISG56-luciferase (ISG56-LUC, central), and ISG54-luciferase (ISG54-LUC, right). A dose-dependent induction of the gene verified the high-throughput screening of "hit" compounds (Compound 1 of Table 1). RLU = relative luciferase unit. Figure 1B demonstrates the specificity of Compound 1, which is 10 μM of this compound (Compound 1) compared to the vehicle control (DMSO) and the equivalent dose of the positive control compound (CPD X). A non-specific β-actin promoter was induced. Figure 1C shows that an increasing amount of Compound 1 treated HeLa cells showed a dose-dependent increase in translocation of interferon regulatory factor (IRF)-3 to the nucleus by subtracting cytoplasmic strength from nuclear strength ("normalization" The nuclear strength") is quantified. Figure 1 D shows that an increasing amount of Compound 1 treated HeLa cells showed a dose-dependent increase in NFκB translocation, which was quantified by nuclear strength minus cytoplasmic strength. "SeV" refers to Sendai virus infection (positive control).

Figures 2A-2C show gene expression induced by compounds 1 and 2 of Table 1. Figure 2A shows that IFIT cells were treated with 10 μM of Compound 1 (grey; OAS1 only) or 10 μM of Compound 2 (black; showing both IFIT2 and OAS1) after IFIT2 (left) and OAS1 (right) over time (from 4 hours to 24) Hour) The degree of gene expression. Figure 2B shows the degree of gene expression of IFIT2 in PH5CH8 cells (solid color bars) and HeLa cells (black check bars) treated with 10 μM of Compound 1 (CPD 1) or Compound 2 (CPD 2). 2C shows the degree of gene expression of IFIT2 (left), OAS1 (central), and MxA (right) in primary HUVEC cells treated with 1 μM Compound 1 (CPD 1) or 1 μM Compound 2 (CPD 2).

Figures 3A-3B show gene expression induced by Compound 3 and Compound 7 of Table 1. Figure 3A shows the IFIT2 gene expression induced by 5 μM Compound 3 or Compound 7. Figure 3B shows Compound 3 induced congenital immune gene expression in mouse macrophage cells.

Figure 4 shows the induction of chemokines IL-8, MCP-1, MIP-1α and MIP-1β by dendritic cells treated with Compound 1 of Table 1 (concentration expressed in μM). LPS is shown to be a positive control inducer of chemokine expression.

Figure 5 shows the results of an experiment performed using the protocol of Example 8, which demonstrates that the selected compound of Figure 5, which is resistant to the antiviral activity of RSV, has antiviral activity. +++ = inhibition of infection greater than 70%, ++ = inhibition of infection greater than 50%, + = inhibition greater than 30%, - = inhibition less than 30%.

Figure 6 shows the antiviral activity of the example compounds against the influenza A virus Udorn/72. Treatment of HEK293 cells with increasing concentrations of Compound 1, Compound 7, Compound 9, and Compound 10 of Table 1 caused dose-dependent inhibition of viral infection (shown as % untreated negative control). The calculated IC ₅₀ value is displayed.

Figure 7 shows the antiviral activity of Compound 5 and Compound 20 of Table 1 against Type 2 dengue virus (DNV). Treatment with an increasing amount of compound showed a dose-dependent reduction in viral infection.

Figure 8 shows the antiviral activity of the example compounds against type 2 DNV. Treatment of Huh 7 cells with increasing concentrations of Compound 8, Compound 3, Compound 5, Compound 6, Compound 7, Compound 9, and Compound 10 of Table 1 caused dose-dependent inhibition of viral infection (shown as untreated negative) Control %). The calculated IC50 value is displayed.

Figure 9 shows the antiviral activity of the example compounds against human coronavirus OC43. Treatment with increasing concentrations of Compound 1, Compound 5, Compound 6, and Compound 7 of Table 1 caused dose-dependent inhibition of viral infection (shown as % untreated negative control). The calculated IC50 value is displayed.

Figure 10 shows the results from an exploratory pharmacokinetic (PK) study. Figure 10A, Administration of Compound 3 of Table 1 via the oral (PO) or intravenous (IV) route allows for the detection of compound levels in serum samples that can be obtained up to 250 minutes after treatment. Figure 10B, Compounds were detected in lung tissue 4 hours after treatment with Compound 3 and Compound 7 of Table 1.

Figures 11A-11C show studies performed using the mouse type 1 hepatitis virus (MHV-1) coronavirus model. Treatment with Compound 3 of Table 1 resulted in a reduction in pathological symptoms (including weight loss) following a lethal challenge with MHV-1 (Figure 11A) and an increase in survival (11B). Figure 11C, the virus was reduced in the lungs of animals treated with Compound 3.

Figure 12 shows the in vitro activity of 5 μM of Compound 12 of Table 1 of the present invention against EBOV, which shows that the log in vitro EBOV titer decreased by more than 2.

Figure 13 shows the dose-response activity of Compound 8 of Table 1 against DENV-2 (expressed in FFU/ml).

The present invention provides compounds, pharmaceutical compositions and methods for targeting the viral protein to the viral protein and transferring it to a congenital antiviral response that targets and enhances the host (individual). Such compounds, pharmaceutical compositions and methods may be more effective, less susceptible to viral resistance, cause less side effects, and are effective against a range of different viruses.

The retinoic acid inducible gene 1 (RIG-I) pathway is closely involved in the regulation of innate immune responses to viral infections, including RNA viral infections. RIG-I is a cytosolic pathogen recognition receptor necessary to trigger immunity against a wide range of RNA viruses. RIG-I is a double-stranded RNA helicase that binds to a motif in the RNA viral genome characterized by the extension of a homopolymer of uridine or a polymeric U/A motif. Binding to RNA-induced conformational changes that attenuate the RIG-I signaling repression of the autorepressor domain, thereby allowing RIG-I to activate and recruit the domain (CARD) to downstream of the signal by means of its tandem caspase activation . RIG-I signaling is dependent on its NTPase activity, but does not require a helicase domain. RIG-I signaling is silenced in resting cells, and the repressor domain acts as an on-off switch in response to viral infection management signaling.

Without being bound by theory or specific mechanism of action, RIG-I signaling is transduced by IPS-1 (also known as Cardif, MAV, and VISA), which is the basic adaptor protein that resides in the outer mitochondrial membrane. IPS-1 recruits a macromolecular signaling complex that stimulates downstream activation of IRF-3, a transcription factor that induces type I interferon (IFN) and the expression of a viral response gene that controls infection. Compounds that trigger RIG-I signaling, either directly or by means of modulation of RIG-I pathway components (including IRF-3), are attractive therapeutic applications as antiviral agents and immunomodulators.

In certain embodiments, high throughput screening methods are used to identify compounds that modulate the RIG-I pathway. In a specific embodiment, the verified RIG-I antagonist lead compound is shown to specifically activate IRF-3. In other embodiments, the compounds have one or more of the following advantages: they induce the expression of an interferon stimulating gene (ISG), which has low cytotoxicity in cell-based assays, which is suitable for simulation development and SAR Research, it has similar drugs Physiological and chemical properties, and / or its resistance to viruses (including dengue virus (DNV), human coronavirus (SARS and MERS-like pathogens), influenza A virus, respiratory syncytial virus (RSV) and / or hepatitis C virus (HCV)) Antiviral activity. In other embodiments, the compounds exhibit anti-viral activity against dsDNA viruses, including human cytomegalovirus. In certain embodiments, the compounds exhibit all of these properties.

The disclosed compounds represent a new class of antiviral therapeutics. Although the invention is not limited by the particular mechanism of action of the compound in vivo, the compound is selected for its modulation of the innate immune antiviral response. In certain embodiments, the modulation is activation of the RIG-I pathway. The compounds, pharmaceutical compositions and methods disclosed herein are useful for reducing one or more of the following, viral proteins, viral RNA, and infectious viruses in laboratory models of viral infection.

The present invention relates to a class of compounds represented by Formula 1:

Wherein L can be NR ² , O, S, C(=O)N, CR ² R ³ CR ² R ³ , CR ² R ³ NR ² , CR ⁴ =CR ⁴ , CR ² R ³ O, CR ² R ³ S, NR ² CR ² R ³ , NR ² C(=O), NS(O) _t , OCR ² R ³ , SCR ² R ³ ; V system (CR ² R ³ ) _u , C(=O)CR ² R ³ , CR ² R ³ O, CR ² R ³ OCR ² R ³ , CR ⁴ =CR ⁴ , C≡C, C(=NR ² ) or C(=O); Q can be NR ² , O, S (O) _t or bond; t = 0, 1, 2; u = 0-3; wherein the dotted line indicates the presence or absence of a bond; R ¹ may be R ^a , OR ² or NR ² R ³ ; each R ^a Optionally, H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² and R ³ may each independently be R ^a , C(=O)R ^a Or SO ₂ R ^a , R ² and R ³ may form optionally substituted carbocyclic, heterocarbocyclic, aryl or heteroaryl rings; each R ⁴ may independently be R ² , OR ^a , C (= O) R ^a , C(=O)NR ² R ³ , NR ² R ³ , NR ^b (=O)R ^a , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , SO ₂ NR ² R ^3, NCOR ^a, halo, trihalomethyl, CN, S = O, or a nitro group; W is and X may each independently be ^{N, NR a, NR 5,} O, S, CR 2 R 4 or CR ^4; R ⁵ can be R ^a , C (=O)R ^a , SO ₂ R ^a or absent; Y ¹ , Y ² , Y ³ and Y ⁴ may each independently be CR ⁴ or N; and NR ² R ³ may form an optionally substituted heterocyclic ring Or a heteroaryl ring (including but not limited to pyrrolidine, hexahydropyridine, morpholine and hexahydropyrazine).

In an embodiment, in the case of Formula 1, Y ¹ may be CR ⁴ or N. For example, Y ¹ can be CR ⁴ .

In an embodiment, in the case of Formula 1, Y ² may be CR ⁴ or N. For example, Y ² can be CR ⁴ .

In an embodiment, it is in terms of Formula 1, Y ² may be CR ⁴ or N. For example, Y ³ can be CR ⁴ .

In the embodiment, in the case of Formula 1, both Y ¹ and Y ² may be CR ⁴ , and in some cases, Y ¹ and Y ² may form a fused heteromixar substituted by R ⁶ as shown below. ring:

Wherein R ⁶ may be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , morpholinyl, CH ₂ C≡CH or NO ₂ . For example, R ⁶ can be H or CH ₃ .

In the embodiment, in the case of Formula 1, Y ³ and Y ⁴ may be CR ⁴ or N. For example, Y ³ and Y ⁴ may be CR ⁴ .

In an embodiment, it is in terms of Formula ^{1, Y 1, Y 2, Y} 3 and Y ⁴ may be a CR ^4. In some cases, Y ¹ , Y ² , Y ^{3 ,} and Y ⁴ may be CH. In some cases, Y ¹ and Y ² may form a fused heterocyclic ring as defined above, optionally substituted with R ⁶ , and Y ³ and Y ⁴ may be CH.

The invention also relates to a class of compounds represented by Formula 1A.

Wherein W can be O or S; and R ¹ can be R ^a , OR ² or NR ² R ³ . R ¹ , R ² , R ³ , R ⁴ , R ^a and V and W may be as defined above for Formula 1. In embodiments, each R ^a may independently be H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² and R ³ may each independently be R ^a , COR ^a or SO ₂ R ^a ; each R ⁴ may independently be R ² , OR ^a , NR ² R ³ , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , NCOR ^a , C ( =O)R ^a , CONR ² R ³ , halogen, trihalomethyl, CN, S=O or nitro; V can be CR ² R ³ , C(=O), C(=O)CR ² R ³ Or C(=N)R ² ; and W can be O or S. In some cases, V can be C=O, and R ¹ can be an optionally substituted aryl or an optionally substituted heteroaryl. For example, R ¹ may be an optionally substituted phenyl group, or R ¹ may be an optionally substituted naphthyl group.

The invention also relates to a class of compounds represented by Formula 1B.

Wherein W can be O or S; and R ¹ may be R ^a or NR ² R ^3. R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^a and V are as defined above for formula 1.

In some cases, V can be C=O, and R ¹ can be an optionally substituted aryl or an optionally substituted heteroaryl. For example, R ¹ may be an optionally substituted phenyl group, or R ¹ may be an optionally substituted naphthyl group.

The invention also relates to a class of compounds represented by formula 1C.

Wherein W can be O or S; and R ¹ can be R ^a , OR ² or NR ² R ³ . R ¹ , R ² , R ³ , R ⁴ , R ^a and V and W are as defined above for Formula 1. In embodiments, each R ^a may independently be H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² and R ³ may each independently be R ^{a, C (= O) R} a or SO ₂ R ^a; each R ⁴ may be independently ^{R 2, oR a, NR 2} R 3, SR a, SOR a, SO 2 R a, SO 2 NHR a, NCOR ^a , C(=O)R ^a , CONR ² R ³ , halogen, trihalomethyl, CN, S=O or nitro; V can be CR ² R ³ , C(=O), C(=O CR ² R ³ or C(=N)R ² ; and W may be O or S. In some cases, V can be C=O, and R ¹ can be an optionally substituted aryl or an optionally substituted heteroaryl. For example, R ¹ may be an optionally substituted phenyl group, or R ¹ may be an optionally substituted naphthyl group.

A class of target compounds can include a compound of Formula 1A, 1B or 1C, wherein R ⁴ can be H; and V can be C=O. Some embodiments may comprise a compound of formula. 1A, 1B, or of formula having the formula 1C in which R ¹ is optionally substituted phenyl-based or optionally substituted naphthyl group of the substituted. Various embodiments can include compounds having Formula 1A, Formula 1B, or Formula 1C, wherein W is S and X is N. Other embodiments may include compounds having Formula 1A, Formula IB or Formula 1C wherein W is O and X is N.

The invention also includes a class of compounds represented by any of Formulas 2 through 11.

Equation 5

Example embodiments may include a compound having the formula 4, in which R ¹ may be substituted with at least one of halogen, phenyl, NR ² R ³ substituent of phenyl, SO ^₂ NR ₂ R ^3, CR ² R ³ ORd substituted benzene of group, non-substituted naphthyl group, the _{^{O (CR 2 R 3) n}} R d, NR a (CR 2 R 3) n R d, NR a (CR 2 R 3) n NR 2 R 3 substituent of the naphthyl group , include pyridyl and phenyl rings of the two structures, or a structure comprising two phenyl rings and the dioxolanyl; each R ^a is independently H or an optionally substituted hydrocarbon group of (C ₁ -C ₁₀ ); R ² and R ³ may each independently be R ^a , COR ^a , (CH 2 ) _n O or SO ₂ R ^a ; each R ⁴ may independently be R ^a ; R ^d may be phenyl or morpholine group; R ⁵ may be H or CH _3; R ⁶ can be H or CH _3; and wherein n may be 3 or 4.

Particular embodiments having Formula 4 can be represented by the following compounds:

Example embodiments may include compounds having the formula 5, in which R ¹ may be substituted with at least one of halogen, phenyl, substituted phenyl of the NR ² R ^3, substituted by SO ₂ R ^d of phenyl, optionally substituted with O (CR ² R ³ ) _n R ^d substituted naphthyl or unsubstituted naphthyl, each R ^a may independently be H or optionally substituted C ₁ -C ₁₀ hydrocarbyl; R ² , R ³ and each R ⁴ may independently be R ^a , R ^d may be optionally substituted phenyl or optionally substituted morpholinyl; R ⁵ may be H or CH ₃ ; R ⁶ may be H or CH ₃ , and wherein n Can be 1, 2, 3 or 4.

Particular embodiments having Formula 4 can be represented by the following compounds:

In various embodiments, the compound can be represented by the following formula

Wherein R ⁴ may be R ^d , SO ₂ R ^d , C(=O)R ^d , NH C(=O)R ^d , R ^e , OR ^c or CF ₃ , wherein R ^c may be H or C ₁ -C _{a 10} hydrocarbon group, R ^d may be a substituted heterocyclic ring, an unsubstituted heterocyclic ring or an unsubstituted carbocyclic ring, and R ^e may be a substituted heteroaryl group or a substituted phenyl group; and n may be 1 Or 2. In a particular embodiment, R ⁴ can be CF ₃ , OR ^c or a phenyl group substituted with at least one OCH ₃ group.

Additionally, some embodiments of Formula 1D may include compounds represented by

Wherein R ⁴ may be: (i) C(=O)R ^d and R ^d is a pyrrolidinyl group, (ii) SO ₂ R ^d and R ^d is a hexahydropyridyl group, (iii) NHC(=O)R ^d and R ^d are phenyl or furyl, (iv) imidazolyl, or (v) thiazolyl.

Furthermore, some embodiments of Formula 1D may include compounds represented by

Wherein X can be NH or O.

Embodiments of Formula 1D can include compounds represented by

In an embodiment, the compound can be represented by the following formula

Wherein each R ⁴ may independently be R ² , OR ^a , NR ² R ³ , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , NCOR ^a , C(=O)R ^a , CONR ² R ³ , halogen, trihalomethyl, CN, S=O or nitro and n=1-4. In some embodiments, R ⁴ can be an optionally substituted heteroaryl. Further, R ⁴ may be optionally substituted by the heteroaryl and n may be 1. In various embodiments, the compound can be represented by the following formula

For any relevant structural feature herein, each R ^a may independently be H; optionally substituted hydrocarbyl, such as C _1-12 or C _1-6 hydrocarbyl; optionally substituted aryl, eg, Substituted C _6-12 aryl, including optionally substituted phenyl; optionally substituted heteroaryl, including optionally substituted C _2-12 heteroaryl, such as optionally substituted pyridine a furyl group which may be substituted, optionally substituted thienyl, or the like. In some embodiments, each R ^a may independently be H or C _1-12 alkyl, including: a straight or branched alkyl group having the formula C _a H _a+1 , or having the formula C _a H _{a a} cycloalkyl group of _-1 , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, such as a linear or branched alkyl group of the formula: CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , C ₅ H ₁₁ , C ₆ H ₁₃ , C ₇ H ₁₅ , C ₈ H ₁₇ , C ₉ H ₁₉ , C ₁₀ H _{21 ,} etc., or the following formula Cycloalkyl: C ₃ H ₅ , C ₄ H ₇ , C ₅ H ₉ , C ₆ H ₁₁ , C ₇ H ₁₃ , C ₈ H ₁₅ , C ₉ H ₁₇ , C ₁₀ H ₁₉ and the like.

In the case of R ^a , in some embodiments, an aryl group can be substituted by halogen, trihalomethyl, alkoxy, alkylamino, OH, CN, alkylthio, arylthio, amidene, Arylsulfonyl, alkylsulfonyl, carboxylic acid, nitro or mercaptoamine.

In the case of R ^a , in some embodiments, the heteroaryl group can be unitary or fused. In some embodiments, a single heteroaryl group can be an imidazole. In some embodiments, the fused heteroaryl group can be benzimidazole. In some embodiments, a heteroaryl group can be substituted with halogen, trihalomethyl, alkoxy, alkylamino, OH, CN, alkylthio, arylthio, anthracene, arylsulfonyl An alkylsulfonyl group, a carboxylic acid, a nitro group or a mercaptoamine group. In some embodiments, the alkyl group can be a branched alkyl group, a cycloalkyl group, or a polycyclic alkyl group.

R ^a can, the hydrocarbon group may be an alkyl, alkenyl or alkynyl group. In some embodiments, an alkyl group can be substituted with halogen, trihalomethyl, alkoxy, alkylamino, OH, CN, heteroaryl, alkylthio, arylthio, anthracene, aryl Sulfhydryl, alkylsulfonyl, carboxylic acid, nitro or mercaptoamine. In some embodiments, the heteroaryl group can be single or fused. In some embodiments, a single heteroaryl group can be an imidazole. In some embodiments, the fused heteroaryl group can be benzimidazole. In some embodiments, an alkenyl group can be a branched alkenyl, cycloalkenyl or polycycloalkenyl group. In some embodiments, an alkenyl group can be substituted by halogen, trihalomethyl, alkoxy, alkylamino, OH, CN, heteroaryl, alkylthio, arylthio, anthracene, aryl Sulfhydryl, alkylsulfonyl, carboxylic acid, nitro or mercaptoamine.

For any of the related structural features herein, R ^b may be H or a C _1-3 hydrocarbyl group, such as CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopropyl, CH=CH ₂ , CH ₂ CH= CH ₂ , C≡CH CH ₂ C≡CH, and the like.

For any of the related structural features herein, R ^c can be H or C _1-3 alkyl, such as CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopropyl, and the like. In some embodiments, R ^c can be H.

For any correlation or structure depicted herein (eg, Formula 1, Formula 2, Formula 3, or Formula 4), R ¹ can be R ^a , OR ^{2 ,} or NR ² R ³ . In some embodiments, R ¹ can be an optionally substituted phenyl group. In some embodiments, R ¹ can be an unsubstituted phenyl group. In some embodiments, R ¹ is optionally substituted may be a group of naphthyl. In some embodiments, R ¹ can be an unsubstituted naphthyl group. In other embodiments, R ¹ can be

In some embodiments, R ¹ can be

In some embodiments, R ¹ can be

In some embodiments, R ¹ can be

In some embodiments, R ¹ can be

In some embodiments, R ¹ can be

In some embodiments, R ¹ can be

For any of the related structural features herein, R ² can be R ^a , COR ^a or SO ₂ R ^a . In some embodiments, R ² can be H, methyl, ethyl, propyl (eg, n-propyl, isopropyl, etc.), cyclopropyl, butyl, cyclobutyl or isomers thereof, pentyl , cyclopentyl or an isomer thereof, hexyl, cyclohexyl or an isomer thereof. In some embodiments, R ² can be H.

For any of the related structural features herein, R ³ can be R ^a , C(=O)R ^a or SO ₂ R ^a . In some embodiments, R ³ can be H, methyl, ethyl, propyl (eg, n-propyl, isopropyl, etc.), cyclopropyl, butyl, cyclobutyl or isomers thereof, pentyl , cyclopentyl or an isomer thereof, hexyl, cyclohexyl or an isomer thereof. In some embodiments, R ³ can be H.

For any of the structural features herein, each R ⁴ may independently be R ² , OR ^a , C(=O)R ^a , CO ₂ R ^a , OCOR ^a , CONR ² R ³ , NR ² R ³ , NR ^b C(=O)R ^a , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , SO ₂ NR ^a R ^b , NC(=O)R ^a , halogen, trihalomethyl, CN , S = O, nitro, or C _2-5 heteroaryl group. In some embodiments, R ⁴ can be H.

In general, R ⁵ and R ⁷ -R ²² may be H or any substituent, for example having 0 to 6 carbon atoms and 0 to 5 independently selected from O, N, S, F, Cl, Br and I. A hetero atom and/or a substituent having a molecular weight of from 15 g/mol to 300 g/mol. Any of R ⁵ and R ⁷ -R ²² may comprise: a) one or more alkyl moieties optionally substituted by the following or, optionally, by the following: b) one or more functional groups Base, for example C=C, C≡C, CO, CO ₂ , CON, NCO ₂ , OH, SH, O, S, N, N=C, F, Cl, Br, I, CN, NO ₂ , CO ₂ H, NH ₂ or the like; or may be a substituent having no alkyl moiety, such as F, Cl, Br, I, NO ₂ , CN, NH ₂ , OH, COH, CO ₂ H, and the like.

For any of the related structural features herein, R ⁵ may be R ^a , COR ^a , SO ₂ R ^a or may be absent. Some examples of R ⁵ may include H or C _1-3 alkyl, such as CH ₃ , C ₂ H ₅ , C ₇ , cyclopropyl, and the like. In some embodiments, R ⁵ can be CH ₃ . In some embodiments, R ⁵ is H.

For any of the above related formulas or structures, some examples of R ¹⁹ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹⁹ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹⁹ can be H.

For any of the above related formulas or structures, some examples of R ⁵ may include R ^b or C(=O)R ^b , CO ₂ R ^b , C(=O)NR as shown below. ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN or C _2-5 heterocyclic group. In some embodiments, R ⁵ can be H, CH ₃ , CH ₂ CH ₃ , SO ₂ NH ₂ or CH ₂ C≡CH. In some embodiments, R ⁵ can be H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH=CH ₂ or CH ₂ C≡CH. In some embodiments, R ⁵ is CH ₂ C≡CH. In some embodiments, R ⁵ can be H.

For any of the above related formulas or structures, some examples of R ⁷ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ⁷ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ⁷ can be H.

For any of the above related equations or structural diagrams, some examples of R ⁸ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ⁸ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ⁸ can be H, Cl, or Br. In some embodiments, R ⁸ may be Cl. In some embodiments, R ⁸ can be Br. In some embodiments, R ⁸ can be H.

For any of the above related equations or structural diagrams, some examples R ⁹ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ⁹ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ⁹ can be H, Cl, or SO ₂ NH ₂ . In some embodiments, R ⁹ can be H. In some embodiments, R ⁹ can be Cl. In some embodiments, R ⁹ can be SO ₂ NH ₂ . In some embodiments, R ⁹ can be H.

In some embodiments, R ⁸ and R ⁹ can be combined to form:

For any of the above related equations or structural diagrams, some examples of R ¹⁰ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹⁰ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹⁰ can be H or Cl. In some embodiments, R ¹⁰ can be H. In some embodiments, R ¹⁰ can be Cl. In some embodiments, R ⁸ and R ¹⁰ can be Cl.

For any of the above related equations or structural diagrams, some examples of R ¹¹ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br or I. In some embodiments, R ¹¹ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , CH ₂ C≡CH Or NO ₂ . In some embodiments, R ¹¹ can be H.

In some embodiments, R ⁷ and R ¹¹ can be H. In some embodiments, R ⁷ , R ^{9 ,} and R ¹¹ can be H. In some embodiments, R ⁷ , R ^{10 ,} and R ¹¹ can be H. In some embodiments, R ⁷ , R ⁸ , R ^{10 ,} and R ¹¹ can be H. In some embodiments, R ⁷ , R ⁸ , R ^{9 ,} and R ¹¹ can be H. In some embodiments, R ⁷ , R ⁸ , R ⁹ , R ^{10 ,} and R ¹¹ can be H.

For any of the above related equations or structural diagrams, some examples of R ¹⁵ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br or C _{2 -5} heterocyclic group. In some embodiments, R ¹⁵ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹⁵ can be H.

For any of the above related equations or structural diagrams, some examples of R ¹⁶ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹⁶ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹⁶ can be H.

For any of the above related formulas or structures, some examples of R ¹⁷ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹⁷ can be H, CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹⁷ can be H.

For any of the above related equations or structural diagrams, some examples of R ¹⁸ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹⁸ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , morpholinyl or NO _2. In some embodiments, R ¹⁸ can be H.

In some embodiments, R ¹⁵ , R ¹⁶ , R ^{17 ,} and R ¹⁸ can be H.

For any of the above related formulas or structures, some examples of R ¹² may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹² can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹² can be H or SO ₂ NH ₂ . In some embodiments, R ¹² can be H. In some embodiments, R ¹² may be a SO ₂ NH _2.

For any of the above related equations or structural diagrams, some examples of R ²⁴ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclyl group. In some embodiments, R ¹³ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl or NO ₂ . In some embodiments, R ¹³ can be H.

In some embodiments, R ¹² and R ¹³ can be H.

For any of the above related equations or structural diagrams, some examples of R ²⁰ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^{b, NR b R c, C} (= O) NR b R c, NR b C (= O) R c, SO 2 NR b R c, CF 3, CN, NO 2, F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ²⁰ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ²⁰ can be H, CH ₂ CH ₃ , OCH ₃ , N(CH ₃ ) ₂ , morpholinyl or SCH ₃ . In some embodiments, R ²⁰ can be H. In some embodiments, R ²⁰ can be CH ₂ CH ₃ . In some embodiments, R ²⁰ can be OCH ₃ . In some embodiments, R ²⁰ can be CN(CH ₃ ) ₂ . In some embodiments, R ²⁰ can be morpholinyl. In some embodiments, R ²⁰ may be SCH _3.

For any of the above related formulas or structures, some examples of R ²² may include R ^b , OR ^b , SR ^b , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _{2- 5} heterocyclic group. In some embodiments, R ²² can be H, CH ₃ or CH ₂ CH ₃ . In some embodiments, R ²² can be H.

In some embodiments, R ¹⁹ and R ²² can be H.

Related to any one of the above structural formula or shown terms, R ¹⁴ of some examples may include a ^{R b, OR b, SR b} , C (= O) R b, CO 2 R b, OC (= O) R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br or I. In some embodiments, R ³⁰ can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹⁴ can be H.

For any of the above related formulas or structures, examples of R ¹³ may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹³ can be _{H, CH 3, CH 2 CH} 3, Cl, Br, OH, OCH 3, SCH 3, NH 2, NHCH 3, N (CH 3) 2, SO 2 NH 2, Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹³ can be H.

For any of the above related formulas or structures, some examples of R ¹² may include R ^b , OR ^b , SR ^b , C(=O)R ^b , CO ₂ R ^b , OC(=O)R ^b , NR ^b R ^c , C(=O)NR ^b R ^c , NR ^b C(=O)R ^c , SO ₂ NR ^b R ^c , CF ₃ , CN, NO ₂ , F, Cl, Br, I or C _2-5 heterocyclic group. In some embodiments, R ¹² can be H, CH ₃ , CH ₂ CH ₃ , Cl, Br, OH, OCH ₃ , SCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , SO ₂ NH ₂ , Morpholinyl, CH ₂ C≡CH or NO ₂ . In some embodiments, R ¹² can be H or NO ₂ . In some embodiments, R ¹² can be H. In some embodiments, R ¹² can be NO ₂ .

In some embodiments, R ^14, R ¹³ and R ¹² may be H. In some embodiments, R ¹³ and R ¹² can be H.

As indicated by the list of compounds in Table 1, in some cases, the substituent bonded to the aromatic carbon atom is H.

Specific embodiments of the compounds disclosed herein have the structure shown in Table 1.

Any structure, formula or name of a compound may refer to any stereoisomer or mixture of stereoisomers of the compound, unless stereochemistry is explicitly depicted.

Unless otherwise indicated, any reference to a compound by structure, formula, name or any other means herein includes pharmaceutically acceptable salts, such as sodium, potassium and ammonium salts; prodrugs, such as ester prodrugs; Solid forms, such as polymorphs, solvates, hydrates, and the like; tautomers; isomers; or any other chemical that can be rapidly converted to the compounds described herein under the conditions of the compounds as described herein.

The term "pharmaceutically acceptable salt" as used herein refers to a tissue that is suitable for contact with an individual within the scope of correct medical judgment without excessive toxicity, irritation, and allergic reaction. Proportional benefits/risk ratios of medicinal salts. Pharmaceutically acceptable salts are well known in the art. In one embodiment, the pharmaceutically acceptable salt is a sulfate. For example, S. M. Berge et al., in J. Pharm. Sci., 1977, 66: 1-19, describe pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic acid and sulfonic acid organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid. , maleic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfamic acid, methylsulfonate Acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, beta-hydroxybutyric acid, malonic acid, galactonic acid, and galacturonic acid. Pharmaceutically acceptable acidic/anionic salts also include acetate, besylate, benzoate, bicarbonate, hydrogen tartrate, bromide, calcium edetate, camphor sulfonate, carbonate, chloride , citrate, dihydrochloride, edetate, ethanedisulfonate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamine Acid salt, ethanol thiol- phenyl arsenate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, hydroxyethyl sulfonate Acid salt, lactate, lactobionate, malate, maleate, malonate, mandelate, methanesulfonate (methanesulfonate), methyl sulfate, mucate (mucate ), naphthalene sulfonate, nitrate, pamoate, pantothenate, phosphate/hydrogen phosphate, polygalacturonate, salicylate, stearate, acetal, succinic acid Salt, sulphate, hydrogen sulphate, citrate, tartrate, 8-octoate, tosylate and triethyl iodide.

Suitable pharmaceutically acceptable base addition salts include metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or from N,N'-dibenzylethylenediamine, chloroprocaine ( Organic salts prepared from chloroprocaine), choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine, arginine and procaine. All of these salts can be used in the usual way The corresponding compounds represented by the disclosed compounds are prepared, for example, by treating the disclosed compounds with a suitable acid or base. Pharmaceutically acceptable basic/cationic salts also include diethanolamine, ammonium, ethanolamine, hexahydropyrazine and triethanolamine salts.

Pharmaceutically acceptable salts include any salt that is retained for the activity of the parent compound and is received for medical use. A pharmaceutically acceptable salt also refers to any salt that can be formed in vivo by administration of an acid, another salt, or a drug that is converted to an acid or a salt.

Prodrugs include compounds which, upon administration, are converted to therapeutically active compounds by hydrolysis of, for example, an ester group or some other biologically labile group.

"Functional group" refers to an atom or group of atoms having similar chemical properties whenever they occur in different compounds, and thus the functional group defines the physical and chemical properties of the family of organic compounds.

Unless otherwise indicated, any compound or chemical structural feature (collectively referred to herein as "compound") (eg, alkyl, aryl, etc.) is referred to as "optionally substituted" and the compound may have no substitution. A base (in this case "unsubstituted"), or it may include one or more substituents (in this case "substituted"). The term "substituent" has the usual meanings known to those skilled in the art. In some embodiments, the substituents may be the usual organic moieties known in the art, and the molecular weight (eg, the sum of the atomic masses of the atoms of the substituents) may range from 15 g/mol to 50 g/mol, from 15 g/mol to 100 g/ Mol, 15 g/mol to 150 g/mol, 15 g/mol to 200 g/mol, 15 g/mol to 300 g/mol or 15 g/mol to 500 g/mol. In some embodiments, the substituents include: 0-30, 0-20, 0-10, or 0-5 C atoms; and/or 0-30, 0-20, 0-10, or 0-5 heteroatoms Including N, O, S, Si, F, Cl, Br or I; the prerequisite is that the substituent in the substituted compound includes at least one atom, including C, N, O, S, Si, F, Cl, Br or I . Examples of the substituent may include an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, a hydroxyl group, an alkoxy group, an aryloxy group, a decyl group, an anthracene group. Base, alkyl carboxylate, mercaptan, alkylthio, cyano, halo, thiocarbonyl, O-amine, mercapto, N-amine, mercapto, O-thiamine N-thiamine, mercapto, C-nonylamino, N-decylamine, S-sulfonylamino, N-sulfonylamino, isocyanato, thiocyanyl, isocyanothio, nitro , mercapto, oxysulfoxide, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino, amine, and the like. For convenience, the term "molecular weight" with respect to a moiety (moiety or part) of a molecule indicates the sum of the atomic masses of the atoms in the portion of the molecule, even though it may not be a complete molecule.

"Hydrocarbon group" has the broadest meaning commonly understood in the art and may include a portion consisting of carbon and hydrogen. Some examples may include alkyl, alkenyl, alkynyl, aryl, and the like, and combinations thereof, and may be a linear hydrocarbon group, a branched hydrocarbon group, a cyclic hydrocarbon group, or a combination thereof. Hydrocarbon group may be bonded to any other number of portions (e.g., a may be bonded to another group, e.g. -CH _3, -CH = CH ₂ and the like; the other two groups, for example, - phenyl -, - C≡C The structure of the moieties may have, and in some embodiments may contain from 1 to 35 carbon atoms. Examples of the hydrocarbon group include a C ₁ alkyl group, a C ₂ alkyl group, a C ₂ alkenyl group, a C ₂ alkynyl group, a C ₃ alkyl group, a C ₃ alkenyl group, a C ₃ alkynyl group, a C ₄ alkyl group, a C ₄ alkenyl group, and C. ₄ alkynyl, C ₅ alkyl, C ₅ alkenyl, C ₅ alkynyl, C ₆ alkyl, C ₆ alkenyl, C ₆ alkynyl, phenyl, and the like.

"Alkyl" has the broadest meaning as commonly understood in the art and may include moieties of carbon and hydrogen that do not contain a double or triple bond and do not have any cyclic structure. The alkyl group can be a linear alkyl group, a branched alkyl group, a cycloalkyl group, or a combination thereof, and in some embodiments, can contain from 1 to 35 carbon atoms. In some embodiments, an alkyl group can include a C _1-10 linear alkyl group, such as methyl (-CH ₃ ), ethyl (-CH ₂ CH ₃ ), n-propyl (-CH ₂ CH ₂ CH ₃ ) , n-Butyl (-CH ₂ CH ₂ CH ₂ CH ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) And C _{3-10 having} a branched alkyl group such as C ₃ H ₇ (for example, isopropyl), C ₄ H ₉ (for example, having a branched butyl isomer), C ₅ H ₁₁ (for example, having a branch) a chain amyl isomer), C ₆ H ₁₃ (for example, a branched hexyl isomer), C ₇ H ₁₅ (for example, a branched heptyl isomer), and the like; a C _3-10 cycloalkyl group, For example, C ₃ H ₅ (e.g., cyclopropyl), C ₄ H ₇ (e.g., cyclobutyl isomer such as cyclobutyl, methylcyclopropyl, etc.), C ₅ H ₉ (e.g., cyclopentyliso) a structure such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C ₆ H ₁₁ (eg, cyclohexyl isomer), C ₇ H ₁₃ (eg, cycloheptyl isomer) And the like; C _3-12 bicycloalkyl, such as decahydronaphthyl and norbornyl; and the like.

"Alkyl", "alkenyl" and "alkynyl" refer to substituted and unsubstituted alkyl, alkenyl and alkynyl groups, respectively. Alkyl groups can be optionally substituted as defined herein.

Substituted alkyl, alkenyl and alkynyl refers to alkyl, alkenyl and alkynyl groups substituted by 1 to 5 substituents including: H, alkyl, aryl, alkenyl, alkynyl, aryl Alkyl, alkoxy, aryloxy, arylalkoxy, alkoxyalkylaryl, alkylamino, arylamine, NH ₂ , OH, CN, NO ₂ , OCF ₃ , CF ₃ , F, 1-indenyl, 2-indenyl, alkylcarbonyl, morpholinyl, hexahydropyridyl, dioxoalkyl, pyranyl, heteroaryl, furyl, phenylthio, tetrazole , thiazolyl, isothiazolyl, imidazolyl, thiadiazolyl, thiadiazole S-oxide, thiadiazole S, S-dioxide, pyrazolo, oxazolyl, isoxazolyl, pyridyl , pyrimidinyl, quinolyl, isoquinolyl, SR, SOR, SO ₂ R, CO ₂ R, COR, CONR'R", CSNR'R" and SO _n NR'R". As used herein, R , R 'and R "may comprise R groups set forth in the present invention, for example ^{R a, R b, R c} , R d, R e, R 2 or R ^3.

"Alkynyl", alone or in combination, means a functional group comprising a straight or branched hydrocarbon having from 2 to 20 carbon atoms and having one or more carbon-carbon triple bonds and having no cyclic structure. An alkynyl group can be optionally substituted as defined herein. Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butynyl, butyn-1-yl, butyn-2-yl, 3-methylbutyn-1-yl, pentynyl, Pentyn-1-yl, hexynyl, hexyn-2-yl, heptynyl, octynyl, decynyl, decynyl, undecynyl, dodecynyl, tridecyne A group, a tetradecynyl group, a fifteen alkynyl group, a hexadecanyl group, a heptadecanyl group, an octadecynyl group, a nineteen alkynyl group, an eicosyl alkynyl group, and the like.

"Alkylene" alone or in combination, means a saturated aliphatic group derived from a straight-chain or branched saturated hydrocarbon at two or more positions of attachment, such as methylene (-CH ₂ -). Unless otherwise stated, "alkyl" may include "alkylene."

"Alkylcarbonyl" or "alkylalkyl", alone or in combination, means a functional group including an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of the alkylcarbonyl group may include a methylcarbonyl group, an ethylcarbonyl group, and the like.

"Heteroalkyl" means, independently or in combination, a functional group comprising a linear, branched or cyclic hydrocarbon having from 1 to 20 atoms bonded by a single bond, wherein at least one atom of the chain is carbon and At least one atomic system O, S, N or any combination thereof in the chain. Heteroalkyl groups can be fully saturated or contain from 1 to 3 degrees of unsaturation. At the non-carbon atoms may be in either an internal position of the heteroalkyl group, and up to two non-consecutive carbon atoms may be based, for example, -CH ₂ -NH-OCH _3. In addition, non-carbon atoms may be oxidized as appropriate and nitrogen may be quaternized by quaternary conditions. Examples of heteroalkyl groups may include morpholine, azadecane, tetrahydrofuran, and the like.

"Alkyloxy" or "alkoxy", alone or in combination, means a functional group including an alkyl ether group. Examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a second butoxy group, a third butoxy group, and the like.

"Hydroxy" means a functional hydroxyl group (-OH), either alone or in combination.

"Carboxy or carboxy", alone or in combination, means a functional group -C(=O)OH or a corresponding "carboxylate" anion-C(=O)O-. Examples include formic acid, acetic acid, oxalic acid, and benzoic acid. "O-carboxy" means a carboxy group of the formula RCOO wherein R is an organic moiety or group. "C-carboxy" refers to a carboxy group of the formula COOR wherein R is an organic moiety or group.

"Sideoxy" means "functional group" = O, either alone or in combination.

"Carbocycle" has the broadest meaning commonly understood in the industry and includes rings or ring systems in which the ring atoms are all carbon. Examples may include phenyl, naphthyl, anthracenyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and the like, and combinations thereof.

"Heterocycle" has the broadest meaning as commonly understood in the art and includes ring or ring systems in which at least one of the ring atoms is not carbon (eg, N, O, S, etc.). Examples can include miscellaneous Aryl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, cyclic heteroalkyl, and the like, and combinations thereof. Examples of the heterocyclic ring system may include quinoline, tetrahydroisoquinoline, tetrahydropyran, imidazole, thiophene, dihydrobenzofuran, and the like.

"Cycloalkyl", "carbocyclylalkyl" and "carbocycloalkyl", alone or in combination, are meant to include non-co-bonds having from 3 to 12 carbon atoms in a carbocyclic structure using only a single bond of carbon and carbon. A functional group of a substituted or unsubstituted non-aromatic hydrocarbon having a conjugated cyclic molecular ring structure. The cycloalkyl group can be monocyclic, bicyclic or polycyclic, and optionally includes from 1 to 3 additional ring structures, such as aryl, heteroaryl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl.

"Low carbon number cycloalkyl", whether alone or in combination, means a monocyclic substitution comprising a non-conjugated cyclic molecular ring structure having from 3 to 6 carbon atoms in a carbocyclic structure using only a single carbon-carbon bond. An unsubstituted non-aromatic hydrocarbon functional group. Examples of the lower carbon cycloalkyl group may include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

"Aryl" has the broadest meaning commonly understood in the art and can include aromatic or aromatic ring systems. The aryl group can be monocyclic, bicyclic or polycyclic, and can optionally include from 1 to 3 additional ring structures; for example, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl. The term "aryl" includes phenyl (phenyl methine), phenylthio, decyl, naphthyl, tolyl, xylyl, decyl, phenanthryl, anthracenyl, biphenyl, naphthyl, 1 -methylnaphthyl, ethanenaphthyl, vinyl naphthyl, anthracenyl, fluorenyl, fluorenyl, phenanthryl, benzo[a]indenyl, benzo[c]phenanthryl, chrysenyl , fluorenyl, fluorenyl, tetracenyl (naphthacenyl), extended triphenyl, anthracene, benzofluorenyl, benzo[a]indenyl, benzo [e] fluorenyl, benzo[ghi]fluorenyl, benzo[j]fluorenyl, benzo[k]fluorenyl, corannulenyl, coronenyl, hydrazinyl (dicoronylenyl), helicenyl, heptaphenyl, hexaphenyl, egg phenyl, pentacene, fluorenyl, fluorenyl, tetraphenylene, and the like.

Further, "aryl", "hydrocarbylaryl" or "aryl hydrocarbon", alone or in combination, may be substituted or unsubstituted aroma including a conjugated cyclic molecular ring structure having 3 to 12 carbon atoms. a functional group of a hydrocarbon. The substituted aryl means an aryl group substituted with 1 to 5 substituents including: H, lower alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, aryl Oxyl, arylalkoxy, alkoxyalkylaryl, alkylamino, arylamine, NH ₂ , OH, CN, NO ₂ , OCF ₃ , CF ₃ , Br, Cl, F, 1 -carbomethyl, 2-methylindenyl, alkylcarbonyl, N-morpholinyl, hexahydropyridyl, dioxoalkyl, pyranyl, heteroaryl, furyl, phenylthio, tetrazolo, Thiazole, isothiazolo, imidazo, thiadiazole, thiadiazole S-oxide, thiadiazole S, S-dioxide, pyrazolo, oxazole, isoxazole, pyridyl, pyrimidinyl, quin Porphyrin, isoquinoline, SR, SOR, SO ₂ R, CO ₂ R, COR, CONR'R", CSNR 'R", SO _n NR'R" and the like.

"Low carbon number aryl" means a functional group including a substituted or unsubstituted aromatic hydrocarbon having a conjugated cyclic molecular ring structure of 3 to 10 carbon atoms, either alone or in combination. Examples of the lower carbon number aryl group may include a phenyl group and a naphthyl group.

"Heteroaryl" means, independently or in combination, a functional group including a substituted or unsubstituted aromatic hydrocarbon having a conjugated cyclic molecular ring structure of 3 to 12 atoms, wherein at least one atom in the ring structure A carbon and at least one atomic system of the ring structure O, S, N, or any combination thereof. The heteroaryl group can be monocyclic, bicyclic or polycyclic, and can optionally include from 1 to 3 additional ring structures, such as aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl. Examples of the heteroaryl group may include an acridinyl group, a benzindenyl group, a benzimidazolyl group, a benzisoxazolyl group, a benzodioxanyl group, a dihydrobenzodioxanyl group. , benzodioxolyl, 1,3-benzodioxolyl, benzofuranyl, benzoisoxazolyl, benzopyranyl, benzophenylthio , benzo[c]phenylthio, benzotriazolyl, benzooxadiazolyl, benzoxazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, carbazolyl, Color keto group, porphyrin group, dihydroporphyrin group, coumarinyl group, dibenzofuranyl group, furopyridinyl group, furyl group, pyridazinyl group, fluorenyl group, indanyl group, imidazolyl group, Carbazolyl, isobenzofuranyl, isodecyl, isoindolyl, dihydroisoindolyl, isoquinolinyl, dihydroisoquinolinyl, isoxazolyl, isothiazolyl, cacao Azolyl, oxadiazolyl, phenanthrene Polinyl, phenanthryl, fluorenyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolinyl, pyrrolyl, pyrrolopyridinyl, quinolinyl, quinacrid Lolinyl, quinazolinyl, tetrahydroquinolyl, tetrazolopyridazinyl, tetrahydroisoquinolyl, phenylthio, thiazolyl, thiadiazolyl, thienopyridinyl, thienyl, phenylthio Base, triazolyl, xanthene and the like.

The phenyl structures associated with some of the embodiments set forth herein are illustrated below. This structure may be unsubstituted, as shown below, or may be substituted such that the substituents may be independently located at any position normally occupied by a hydrogen atom when the structure is unsubstituted. Attachment can be made at any location that is typically occupied by a hydrogen atom unless the attachment point is indicated by -|.

Each R ^a may independently be H; optionally substituted hydrocarbyl; optionally substituted aryl, such as optionally substituted phenyl or optionally substituted aryl; optionally substituted heteroaryl For example, a pyridyl group which may be optionally substituted, a furyl group which may be optionally substituted, a thienyl group which may be optionally substituted, and the like. In some embodiments, each R ^a may independently be H or C _1-12 alkyl, including: straight or branched alkyl, such as a straight or branched alkyl group of the formula: CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , C ₅ H ₁₁ , C ₆ H ₁₃ , C ₇ H ₁₅ , C ₈ H ₁₇ , C ₉ H ₁₉ , C ₁₀ H _{21 ,} etc., or the following formula Cycloalkyl: C ₃ H ₅ , C ₄ H ₇ , C ₅ H ₉ , C ₆ H ₁₁ , C ₇ H ₁₃ , C ₈ H ₁₅ , C ₉ H ₁₇ , C ₁₀ H ₁₉ and the like.

I. Pharmaceutical composition

According to other embodiments, the invention provides a pharmaceutical composition comprising any of the compounds described herein.

A pharmaceutical composition can be obtained by administering a compound disclosed herein, or a pharmaceutically acceptable prodrug or salt thereof, to a pharmaceutically acceptable product suitable for delivery to an individual according to known methods of drug delivery. The carrier is combined to form. Thus, a "pharmaceutical composition" includes at least one of the compounds disclosed herein in association with one or more pharmaceutically acceptable carriers, excipients or diluents, such as being suitable for the chosen mode of administration.

The pharmaceutical composition comprising the compound of the present invention can be formulated into various forms depending on the particular indication being treated, and the pharmaceutical composition will be apparent to those skilled in the art. Formulation of a pharmaceutical composition comprising one or more compounds of the invention can be carried out using a simple medicinal chemical process. The pharmaceutical compositions can be subjected to conventional pharmaceutical procedures (e.g., sterilization) and/or they can contain conventional adjuvants such as buffers, preservatives, isotonic agents, stabilizers, wetting agents, emulsifiers and the like.

Administration of the formulations of the invention can be carried out in a variety of ways, including orally, subcutaneously, intravenously, intracerebroventricularly, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonarily, intrathecalally, intrathecally, Transvaginal, transrectal, intraocular or any other acceptable means. Formulations may be administered continuously by infusion using techniques known in the art, such as a pump (e.g., a subcutaneous osmotic pump) or implantation, but a bolus is acceptable. In some cases, the formulation can be applied directly as a solution or spray.

Examples of pharmaceutical compositions are solutions designed for parenteral administration. While in many cases the pharmaceutical solution formulations provided in liquid form are suitable for immediate use, such parenteral formulations may also be provided in a frozen or lyophilized form. In the former case, the composition must be thawed prior to use. The latter form is generally used to enhance the stability of the active compounds contained in the compositions under a wide variety of storage conditions, as recognized by those skilled in the art that lyophilized formulations are generally more stable than their liquid counterparts. The lyophilized preparations are reconstituted prior to use by the addition of one or more suitable pharmaceutically acceptable diluents, such as sterile water for injection or sterile physiological saline solution.

Parenteral formulations may, if appropriate, conjugated to a compound of the desired purity with one or more pharmaceutically acceptable carriers, excipients or stabilizers commonly employed in the art (all such are referred to as "" Excipient") (for example, buffers, stabilizers, preservatives, isotonic agents, nonionic detergents, antioxidants, and/or other various additives) It is prepared for storage as a lyophilized formulation or aqueous solution.

Buffers help maintain the pH within close proximity to physiological conditions. It is usually present in a concentration ranging from 2 mM to 50 mM of the pharmaceutical composition. Buffers suitable for use in connection with the present invention include both organic and inorganic acids and salts thereof, such as citrate buffers (eg, citrate monosodium-disodium citrate mixture, citric acid-trisodium citrate mixture, lemon) Acid-sodium citrate monosodium mixture, etc.), succinate buffer (eg, succinic acid-succinic acid monosodium mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffer (for example, tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffer (for example, fumaric acid-fumaric acid monosodium mixture, fumaric acid-fumar) a mixture of disodium acid, a mixture of monosodium fumarate and disodium fumarate, etc., a gluconate buffer (for example, a mixture of gluconic acid-sodium gluconate, a mixture of gluconic acid-sodium hydroxide, potassium gluconate-potassium gluconate) Mixture, etc.), oxalate buffer (eg, oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture, etc.), lactate buffer (eg, lactic acid-sodium lactate mixture) Lactic acid - sodium hydroxide mixture, lactic acid - potassium lactate mixture, etc.) and acetate buffers (e.g., acetic acid - sodium acetate mixture, acetic acid - sodium hydroxide mixture, etc.). Further possible are phosphate buffers, histidine buffers and trimethylamine salts (eg Tris).

Preservatives may be added to hinder microbial growth and are typically added in an amount from 0.2% to 1% (w/v). Preservatives suitable for use in connection with the present invention include phenol, benzyl alcohol, m-cresol, methylparaben, propylparaben, octadecyldimethylbenzylammonium chloride, benzalkonium halide (eg, benzalkonium chloride, benzalkonium bromide or benzalkonium iodide), hexamethylene diammonium chloride, alkyl p-hydroxybenzoate (eg methylparaben or propylparaben), adjacent Hydroquinone, resorcinol, cyclohexanol and 3-pentanol.

An isotonic agent may be added to ensure the isotonicity of the liquid composition and it includes a polyhydric sugar alcohol, preferably a ternary or higher sugar alcohol such as glycerol, erythritol, arabitol, xylitol, sorbitol Alcohol and mannitol. The polyol can be between 0.1% and 25% by weight. The relative amounts of the usual components and other components are present in an amount of from 1% by weight to 5% by weight.

Stabilizer refers to a wide variety of excipients that function in the range of fillers to stabilizing therapeutic agents or additives that help prevent denaturation or adhesion to the walls of the container. Typical stabilizers may be polyhydric sugar alcohols (as listed above); amino acids such as arginine, lysine, glycine, glutamic acid, aspartame, histidine, alanine, birds Amine acid, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugar or sugar alcohol, such as lactose, trehalose, stachyose, mannitol, sorbitol, wood Sugar alcohols, ribitol, inositol, galactitol, glycerol and the like, including cyclic polyols such as cyclohexanol; polyethylene glycol; amino acid polymers; sulfur-containing reducing agents such as urea, glutathione Peptide, lipoic acid, sodium thioglycolate, thioglycerol, alpha-monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (ie, <10 residues); proteins, such as human serum albumin, bovine serum white Protein, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides such as xylose, mannose, fructose and glucose; disaccharides such as lactose, maltose and sucrose; and trisaccharides such as cottonseed Sugar; and polysaccharides such as dextran. The stabilizer is usually present in the range of from 0.1 part by weight to 10,000 parts by weight based on the weight of the active compound.

Other various excipients can include fillers (eg, starch), chelating agents (eg, EDTA), antioxidants (eg, ascorbic acid, methionine, and vitamin E) and cosolvents.

Particular embodiments may include one or more of the following: ethanol (<10%), propylene glycol (<40%), polyethylene glycol (PEG) 300 or 400 (<60%), NN-dimethylacetamidine Amine (DMA, <30%), N-methyl-2-pyrrolidone (NMP, <20%), dimethyl hydrazine (DMSO, <20%) cosolvent or cyclodextrin (<40%) It has a pH of 3 to 9.

The compound may also be trapped in, for example, microcapsules prepared by coacervation techniques or by interfacial polymerization (eg, hydroxymethylcellulose, gelatin or poly-(methyl methacrylate) microcapsules), such microcapsules It is in the form of a colloidal drug delivery system (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or a macroemulsion. These techniques are disclosed in Remington, The Science and Practice of Pharmacy, 21st edition, published by Lippincott Williams & Wilkins, A Wolters Kluwer Company, 2005.

Parenteral formulations intended for in vivo administration are generally sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane.

In general, the pharmaceutical compositions may be in solid form (including granules, powders or suppositories) or in liquid form (for example, solutions, suspensions or emulsions). The compound can be combined with an adjuvant (for example, lactose, sucrose, starch powder, cellulose ester of alkanoic acid, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium sulfate and calcium salt, gum arabic, Gelatin, sodium alginate, polyvinylpyrrolidine and/or polyvinyl alcohol are mixed and tableted or encapsulated for conventional administration. Alternatively, it can be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, oil (such as corn oil, peanut oil, cottonseed oil or sesame oil), tragacanth and/or various buffers. Other adjuvants and modes of administration are well known to the pharmaceutical industry. The carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax or other materials well known in the art.

Oral administration of the compounds and compositions is a contemplated practice of the invention. For oral administration, the pharmaceutical compositions may be in solid or liquid form, for example, in the form of capsules, lozenges, powders, granules, suspensions, emulsions or solutions. The pharmaceutical compositions are preferably formulated in the form of dosage units containing the active ingredient. The daily dosage suitable for humans or other individuals can vary widely depending on the condition of the individual and other factors, but can be determined by those skilled in the art using conventional methods.

Solid dosage forms for oral administration can include capsules, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. In normal practice, such dosage forms may also include other materials than inert diluents, such as a lubricant such as magnesium stearate. In the case of capsules, lozenges and nine doses, the dosage form may also include a buffer. Tablets and pills may additionally be prepared with an enteric coating. For buccal administration, the pharmaceutical composition may be formulated in a conventional manner. Or in the form of a diamond lozenge.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water conventionally employed in the art. The pharmaceutical compositions may also include adjuvants such as wetting agents, sweetening, flavoring, and flavoring agents.

The pharmaceutical compositions can be formulated for parenteral administration by injection (e.g., by bolus injection or infusion). Formulations for injection may be presented in unit dosage form in, for example, a glass ampule or a multi-dose container (eg, a glass vial). The pharmaceutical composition for injection may be in the form of a suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain a formulation such as an antioxidant, a buffer, a nonionic detergent, a disintegrating agent, Isotonic agents, suspending agents, stabilizers, preservatives, dispersing agents, and/or other various additives.

While the pharmaceutical compositions provided in liquid form are suitable for immediate use in many cases, such parenteral formulations may also be provided in a frozen or lyophilized form. In the former case, the pharmaceutical composition must be thawed prior to use. The latter form is generally employed to enhance the stability of the compounds contained in the pharmaceutical compositions under a wide variety of storage conditions, as recognized by those skilled in the art, as lyophilized formulations are generally more stable than their liquid counterparts. . Parenteral formulations may, by appropriate means, a compound of the desired purity, together with one or more pharmaceutically acceptable carriers, excipients or stabilizers conventionally employed in the art (all such "excipient" (for example, antioxidants, buffers, nonionic detergents, disintegrants, isotonic agents, suspending agents, stabilizers, preservatives, dispersants, and/or other various additives) Mix to prepare for storage as a lyophilized formulation. The lyophilized preparations are reconstituted prior to use by the addition of one or more suitable pharmaceutically acceptable diluents, such as sterile non-pyrogenic water for injection or sterile physiological saline solution.

For administration by inhalation (for example, nasal or pulmonary), the pharmaceutical composition may conveniently be in the form of an aerosol spray from a pressurized pack or nebulizer and/or by means of a suitable propellant (eg, dichlorodifluoromethane, trichloro Delivery of fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

The compound can be combined with an adjuvant (for example, lactose, sucrose, starch powder, cellulose ester of alkanoic acid, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium sulfate and calcium salt, gum arabic, Gelatin, sodium alginate, polyvinylpyrrolidine and/or polyvinyl alcohol are mixed and tableted or encapsulated for conventional administration. Alternatively, it can be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, oil (such as corn oil, peanut oil, cottonseed oil or sesame oil), tragacanth and/or various buffers. Other adjuvants and methods of administration are well known to the pharmaceutical industry. The carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax or other materials well known in the art.

In addition to the above formulations, the pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations can be administered by implantation or intramuscular injection.

The compound may also be trapped in, for example, microcapsules prepared by coacervation techniques or by interfacial polymerization (eg, hydroxymethylcellulose, gelatin or poly-(methyl methacrylate) microcapsules), such microcapsules It is in the form of a colloidal drug delivery system (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or a macroemulsion. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, A Wolters Kluwer Company, 2005.

Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compound or composition, which matrices are in a suitable form, such as a film or microcapsule. Examples of sustained release matrices include polyesters, hydrogels (eg, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide, L-glutamic acid, and ethyl-L. - a copolymer of glutamate, a non-degradable ethylene-vinyl acetate, a degradable lactic acid-glycolic acid copolymer (eg PROLEASE ^® technology (Alkermes, Cambridge, Massachusetts) or LUPRON DEPOT ^® (copolymerized by lactic acid-glycolic acid) And injectable microspheres composed of leuprolide acetate; Abbott Laboratories, Abbott Park, Illinois) and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid are capable of releasing molecules for long periods of time (eg, for up to 100 days), certain hydrogel-releasing compounds continue for a relatively short period of time.

II. How to use

The pharmaceutical compositions disclosed herein are useful for treating a viral infection in an individual; wherein the viral infection is caused by a virus from one of the following families: Arenaviridae, Arterivirus, stellate Astroviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Closteroviridae, Kidney Bean Comoviridae, Coronaviridae, Cystoviridae, Filamentous genus, Flaviviridae, Flexiviridae, Hepatic Deoxyriboruvirus Hepadnaviridae), Hepatitis virus, Herpesviridae, Leviviridae, Luteoviridae, Mesoniviridae, Mononegavirale, Mosaic Virus (Mosaic Virus), Nidovirale, Nodaviridae, Orthomyxoviridae, Papillomavirus (Pa Pillomaviridae), Paramyxoviridae, Picobirnaviridae, Small Binuclear Virus, Picornaviridae, Potyviridae, Reoviridae Reoviridae), Retroviridae, Roniviridae, Sequiviridae, Tenuivirus, Togaviridae, Tomato Dwarf Virus (Tombusviridae) ), the whole virus family (Totiviridae) and the turnip yellowing mosaic virus family (Tymoviridae).

According to a more specific embodiment, the pharmaceutical composition can be used to treat a viral infection caused by one or more of the following: Alfuy virus, Banzi virus, bovine diarrhea virus, TB virus ( Chikungunya virus), dengue virus (DNV), Encephalomyocarditis virus (EMCV), Hepatitis B virus (HBV), HCV, human cytomegalovirus (hCMV), HIV, Ilheus virus, influenza virus (including Avian and pig isolates, rhinovirus, norovirus, adenovirus, Japanese encephalitis virus, Kokobera virus, Kunjin virus, Kosa Kyasanur forest disease virus, louping-ill virus, measles virus, MERS-coronavirus (MERS), interstitial pneumonia virus, mosaic virus, Murray Valley Murray Valley virus, parainfluenza virus, poliovirus, Powassan virus, respiratory syncytial virus (RSV), Rocio virus, SARS-Coronavirus (SARS), St. Louis encephalitis virus, tick-borne encephalitis virus, WNV, Ebola virus, Nipah virus, Risa virus, Taka Ribe virus (Tacaribe v Irus), Junin virus and yellow fever virus.

In embodiments, a method of treating a viral infection in an individual can comprise administering to the individual a therapeutically effective amount of a pharmaceutical composition having the structure

In some cases, viral infections are caused by the Ebola virus.

Many RNA viruses share biochemical, regulatory, and signaling pathways. These viruses include influenza viruses (including poultry and pig isolates), rhinoviruses, norovirus, DNV, RSV, WNV, HCV, parainfluenza virus, interstitial pneumonia virus, TB virus, SARS, MERS, poliovirus, measles virus, yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray encephalitis Poison, Poisson virus, Rossio virus, sheep jumping virus, Banzi virus, Ilheus virus, Kokobara virus, Kuching virus, Alf virus, bovine diarrhea virus, mosaic virus Either, HIV, Ebola, Reiza virus and Kosano forest disease virus. Such viruses can be treated using the compounds, pharmaceutical compositions and methods disclosed herein.

The antiviral activity against WNV, Nipah virus, Reese fever virus and Ebola virus was measured in vitro by lesion formation assay. Viral strains used in these assays include WNV-TX (WNV), WNV-MAD (WNV), NiV-Malaysia (Nipah), LASV-Josiah (Lessa), and ZEBOV-Mayinga (Ebola). Cultured human cells, including human umbilical vein cells (HUVEC), are seeded in tissue culture plates and infected with the virus at an MOI of 0.01 to 0.5 including, but not limited to, a duration of 2 hours, and then removed. Compound dilutions were prepared in 0.5% DMSO and used to treat cells at a final compound concentration ranging from 0.001 [mu]M/well to 10 [mu]M/well. The vehicle control wells contained 0.5% DMSO and were used for comparison with drug treated cells. The virus infection after the drug treatment is continued for 48 hours to 96 hours. The viral supernatant is then harvested and used to infect a new licensed cell monolayer. The newly infected cells were incubated overnight (18-24 hours) and used to measure the level of infectious virus in the initial supernatant by lesion formation analysis using methods generally known in the art.

The methods disclosed herein comprise treating a subject (human, mammal, free-range animals, veterinary animals (dogs, cats, reptiles, birds, etc.), farm animals, and livestock (horse, cattle, etc.) using the pharmaceutical compositions disclosed herein. Goats, pigs, chickens, etc.) and research animals (monkeys, rats, mice, fish, etc.). Treating an individual includes delivering a therapeutically effective amount. Therapeutically effective amounts include those in which they provide an effective amount, prophylactic treatment, and/or therapeutic treatment.

An "effective amount" is the amount of a compound required to cause a desired physiological change in an individual. An effective amount is usually administered for research purposes. The effective amount disclosed herein reduces, controls or eliminates the presence or activity of a viral infection and/or reduces, controls or eliminates undesirable side effects of viral infection. For example, an effective amount may result in a decrease in the viral protein in an individual or study, an individual or Reduction of viral RNA in the study and/or reduction in virus present in cell culture.

"Prophylactic treatment" includes the administration of an individual to a subject who does not exhibit signs or symptoms of viral infection or who exhibit only early signs or symptoms of viral infection, such that administration therapy is used to reduce, prevent or reduce the risk of further development of viral infection. the goal of. Therefore, prophylactic treatment plays a role in the prevention and treatment of viral infections. Prophylactic treatment may also include vaccines as described elsewhere herein. Prophylactic treatment may result in no increase in viral proteins or RNA in the individual and/or clinical signs of viral infection, such as loss of appetite, fatigue, fever, muscle pain, nausea and/or abdominal pain in the case of HCV; A fever and/or headache in the case of WNV; and cough, congestion, fever, sore throat and/or headache in the case of RSV. Prophylactic treatment can be administered to any individual regardless of the presence or absence of signs of viral infection. In some embodiments, prophylactic treatment can be administered prior to travel.

"Therapeutic treatment" includes administration to an individual who exhibits symptoms or signs of viral infection, and is administered to a system for the purpose of reducing or eliminating signs or symptoms of viral infection. Therapeutic treatment can reduce, control or eliminate the presence or activity of the virus and/or reduce, control or eliminate the side effects of the virus. Therapeutic treatment may reduce the clinical indicators of viral protein or RNA reduction and/or viral infection in an individual, for example: loss of appetite, fatigue, fever, muscle pain, nausea and/or abdominal pain in the case of HCV; In the case of fever and/or headache; and in the case of RSV cough, congestion, fever, cyanosis, sore throat and/or headache.

For administration, a therapeutically effective amount (also referred to herein as a dose) can be initially estimated based on results from in vitro analysis and/or animal model studies. For example, the dosage can be formulated in an animal model to achieve a circulating concentration range (including IC50) as determined for specific targets in cell culture. This information can be used to more accurately determine the useful dose in the individual of interest.

The actual dose administered to a particular individual can be determined by a physician, veterinarian, or researcher, taking into account parameters such as physical and physiological factors, including the target, body weight, and severity of the condition. Degree, type of viral infection, prior or coexisting therapeutic intervention, individual morbidity and route of administration.

The pharmaceutical composition can be administered intravenously to an individual for treatment of a viral infection in a clinically safe and effective manner, including one or more separate administrations of the composition. For example, 0.05 mg/kg to 5.0 mg/kg can be administered to an individual in one or more doses per day (eg, 0.05 mg/kg once daily (QD), 0.10 mg/kg QD, 0.50 mg/kg QD, 1.0 Mg/kg QD, 1.5 mg/kg QD, 2.0 mg/kg QD, 2.5 mg/kg QD, 3.0 mg/kg QD, 0.75 mg/kg twice daily (BID), 1.5 mg/kg BID or 2.0 mg/kg Dose of BID). For certain antiviral indicators, the total daily dose of the compound may range from 0.05 mg/kg to 3.0 mg/kg, administered to the individual 1 to 3 times a day intravenously, including using 60 minutes of QD, BID or three times daily. (TID) intravenous infusion administration of 0.05 to 3.0 mg/kg/day, 0.1-3.0 mg/kg/day, 0.5-3.0 mg/kg/day, 1.0-3.0 mg/kg/day, of the compound of Table 1, A total daily dose of 1.5-3.0 mg/kg/day, 2.0-3.0 mg/kg/day, 2.5-3.0 mg/kg/day, and 0.5-3.0 mg/kg/day. In one embodiment, the antiviral pharmaceutical composition can, for example, have a total daily dose of 1.5 mg/kg, 3.0 mg/kg, 4.0 mg/kg of a composition having up to 92-98% wt/wt of the compound of Table 1 Intravenous QD or BID is administered to the individual.

Other useful doses may generally range from 0.1 [mu]g/kg to 5 [mu]g/kg or from 0.5 [mu]g/kg to 1 [mu]g/kg. In other examples, the dose may include 1 μg/kg, 5 μg/kg, 10 μg/kg, 15 μg/kg, 20 μg/kg, 25 μg/kg, 30 μg/kg, 35 μg/kg, 40 μg/kg, 45 μg/kg, 50 μg/ Kg, 55 μg/kg, 60 μg/kg, 65 μg/kg, 70 μg/kg, 75 μg/kg, 80 μg/kg, 85 μg/kg, 90 μg/kg, 95 μg/kg, 100 μg/kg, 150 μg/kg, 200 μg/kg, 250 μg/kg, 350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 550 μg/kg, 600 μg/kg, 650 μg/kg, 700 μg/kg, 750 μg/kg, 800 μg/kg, 850 μg/kg, 900 μg/ Kg, 950 μg/kg, 1000 μg/kg, 0.1 mg/kg to 5 mg/kg or 0.5 to 1 mg/kg. In other examples, the dose may include 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30. Mg/kg, 35mg/kg, 40mg/kg, 45mg/kg, 50mg/kg, 55mg/kg, 60mg/kg, 65mg/kg, 70mg/kg, 75mg/kg, 80mg/kg, 85mg/kg, 90mg/ Kg, 95mg/kg, 100mg/kg, 150mg/kg, 200mg/kg, 250mg/kg, 350mg/kg, 400mg/kg, 450mg/kg, 500mg/kg, 550mg/kg, 600mg/kg, 650mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, 1000 mg/kg or more.

A therapeutically effective amount can be achieved by administering a single or multiple doses during the course of the treatment regimen (eg, daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, every month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months Every 10 months, every 11 months or every year).

The administration of the pharmaceutical composition of the present invention can be carried out in various ways, including oral, subcutaneous, intravenous, intracerebral, intranasal, transdermal, intraperitoneal, intramuscular, intrapulmonary, intrathecal, intrathecal. , transvaginal, transrectal, intraocular or any other acceptable means. The pharmaceutical composition can be administered continuously by infusion using techniques well known in the art, such as a pump (e.g., a subcutaneous osmotic pump) or implantation, but a bolus is acceptable. In some cases, the pharmaceutical composition can be applied directly as a solution or spray.

Particular embodiments provide pharmaceutical compositions comprising any one or more of the compounds described herein for the purpose of treating and/or preventing a disease in an individual. Other embodiments provide pharmaceutical compositions, either alone or in combination with an antigen. Thus, in some embodiments, the pharmaceutical composition can be used as a vaccine.

The invention provides the use of a compound as an adjuvant.

The compounds, pharmaceutical compositions and methods disclosed herein can be added or synergistic with other therapies currently under development or use. For example, ribavirin and interferon-alpha provide an effective treatment for HCV infection when used in combination. Its combined efficacy can exceed the efficacy of any pharmaceutical product when used alone. The pharmaceutical composition of the present invention may be used alone or in combination with interferon, ribavirin and/or Or a combination of small molecules for viral targets (assembly of viral proteases, viral polymerases and/or viral replication complexes) and host targets (host proteases, viral targets required for viral processing) For example, host kinases required for phosphorylation of NS5A) and inhibitors of host factors necessary for efficient utilization of viral internal ribosome entry sites or IRES have been developed.

The pharmaceutical compositions disclosed herein can be used in combination or in combination with: adamantane inhibitor, neuraminidase inhibitor, alpha interferon, non-nucleoside or nucleoside polymerase inhibitor, NS5A inhibitor, antihistamine , protease inhibitors, helicase inhibitors, P7 inhibitors, entry inhibitors, an IRES inhibitors, immunostimulants, HCV replication inhibitors, cyclophilin inhibitors A, A ₃ adenosine antagonists and / or micro RNA Repressor.

Cytokines that can be administered in combination or in combination with the pharmaceutical compositions disclosed herein include interleukin (IL)-2, IL-12, IL-23, IL-27 or IFN-γ.

New HCV drugs that have been or are potentially useful for combination or co-administration with the pharmaceutical compositions disclosed herein include ACH-1625 (Achillion); glycosylated interferon (Alios Biopharma); ANA598, ANA773 (Anadys Pharm) ATI-0810 (Arisyn Therapeutics); AVL-181 (Avila Therapeutics); LOCTERON® (Biolex); CTS-1027 (Conatus); SD-101 (Dynavax Technologies); Clemizole (Eiger Biopharmaceuticals); GS-9190 (Gilead Sciences); GI-5005 (Global Immune BioPharma); Resiquimod/R-848 (Graceway Pharmaceuticals); Human serum albumin fusion interferon (Albinterferon) alpha-2b (Human Genome Sciences) IDX-184, IDX-320, IDX-375 (Idenix); IMO-2125 (Idera Pharmaceuticals); INX-189 (Inhibitex); ITCA-638 (Intarcia Therapeutics); ITMN-191/RG7227 (Intermune); ITX- 5061, ITX-4520 (iTherx Pharmaceuticals); MB11362 (Metabasis Therapeutics); Bavituximab (Peregrine Pharmaceuticals); PSI-7977, RG7128, PSI 938 (Pharmasset); PHX1766 (Phenomix); Nitazoxanide / ALINIA® (Romark Laboratories); SP-30 (Samaritan Pharmaceuticals); SCV-07 (SciClone); SCY-635 (Scynexis); TT-033 (Tacere Therapeutics); Viramidine/taribavirin (Valeant Pharmaceuticals); Telaprevir, VCH-759, VCH-916, VCH-222, VX-500, VX -813 (Vertex Pharmaceuticals); and PEG-INF λ (Zymogenetics).

New influenza and WNV drugs that have been or are potentially useful for combination or co-administration with the pharmaceutical compositions disclosed herein include neuraminidase inhibitors (Peramivir, Nani) Laninamivir; triple therapy - neuraminidase inhibitor, ribavirin and amantadine (ADS-8902); polymerase inhibitor (Favipiravir); reverse transcriptase Inhibitor (ANX-201); inhaled chitosan (ANX-211); entry/binding inhibitor (binding site mimic, Flucide); entry inhibitor (fludase); fusion inhibitor (for WNV) MGAWN1); host cell inhibitors (lantibiotics); RNA genome cleavage (RNAi, RNAse L); immunostimulatory agents (interferon Alferon-LDO; neurokinin 1 antagonist, Homspera ), interferon Alferon N) for WNV; and TG21.

Other drugs potentially useful in combination with or in combination with pharmaceutical compositions for the treatment of influenza and/or hepatitis include peginterferon alfa-2a (Pegasys), pegylated interferon -2-2b (Peg-Intron), ribavirin (Copegus; Rebetol), oseltamivir (Tamiflu), Zana Zanamivir (Relenza), amantadine and amantadine.

The agents may be included as part of the same pharmaceutical composition or may be administered separately from the compounds of the invention simultaneously or according to another treatment schedule.

The compound or pharmaceutical composition can be added or synergized with other compounds or pharmaceutical compositions To be able to carry out vaccine development. With its antiviral and immunopotentiating properties, the compounds can be used to affect prophylactic or therapeutic vaccination. Compounds are not required to be administered simultaneously or in combination with other vaccine compounds. The vaccine application of the compound is not limited to the treatment of viral infections, but the generality of the immune response elicited by the compound may cover all therapeutic and prophylactic vaccine applications.

A "vaccine" is an immunogenic preparation for inducing an immune response in an individual. The vaccine may have more than one immunogenic component. Vaccines can be used for prophylactic and/or therapeutic purposes. Vaccines do not necessarily have to prevent viral infections. Without being bound by theory, the disclosed vaccine may be such that when a vaccine is administered as described herein, the viral infection affects the individual's immune response in a small amount, including at all, or in a manner that improves the biological or physiological effects of the viral infection. . As used herein, a vaccine includes a formulation for the purpose of treating a viral infection in an individual, including a vertebrate, comprising a pharmaceutical composition comprising the compound alone or in combination with an antigen.

The invention provides the use of a compound and a pharmaceutical composition as an adjuvant. The adjuvant enhances, strengthens, and/or accelerates the beneficial effects of another administered therapeutic agent. In a particular embodiment, the term "adjuvant" refers to a compound that improves the effect of other agents on the immune system. Adjuvants having this function may also be inorganic or organic chemicals, macromolecules or whole cells of certain killed bacteria which enhance the immune response to the antigen. It can be included in a vaccine to enhance the recipient's immune response to the antigen provided.

As is known to those skilled in the art, vaccines are resistant to viruses, bacterial infections, cancer, etc. and may include one or more of the following: live attenuated vaccine (LAIV), inactivated vaccine (IIV; killed viral vaccine). ), subunit (lytic vaccine); subviral particle vaccine; purified protein vaccine; or DNA vaccine. Suitable adjuvants include one or more of the following: water/oil emulsions, nonionic copolymer adjuvants (eg CRL 1005 (Optivax; Vaxcel, Norcross, Ga.)), aluminum phosphate, aluminum hydroxide, hydroxide Aqueous suspensions of aluminum and magnesium hydroxide, bacterial endotoxins, polynucleotides, polyelectrolytes, lipophilic adjuvants, and synthetic mAbs (norMDP) analogs, such as N-ethylidene-nor-cell wall Mercapto-L-alanamine D-isoglutamic acid, N-acetyl-cyanomethyl-(6-O-stearyl)-L-alanamine-D-iso-glutamic acid or N-ethylene glycol- Cell wall thiol-LalphaAbu-D-isoglutamate (Ciba-Geigy Co., Ltd.).

The invention further encompasses the use and use of the compounds and pharmaceutical compositions in many applications in vitro, including the development of anti-viral infection therapies and vaccines, the study of the regulation of innate immune responses in eukaryotic cells, and the like. The compounds of the invention and pharmaceutical compositions can also be used in animal models. The results of such in vitro and in vivo use of the compounds and pharmaceutical compositions can, for example, be informed of their in vivo use in humans, or can be of value independent of any human therapeutic or prophylactic use.

The following examples are included to demonstrate specific embodiments of the invention. It will be apparent to those skilled in the art that <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; For example, the following examples provide in vitro methods for testing compounds of the invention. Other in vitro and/or in vivo viral infection models include flaviviruses (eg, DNV, bovine diarrhea virus, WNV, and GBV-C viruses), other RNA viruses (eg, RSV, SARS, and HCV replication subsystems). In addition, any suitably cultured cell component for viral replication can be used in antiviral assays.

Experimental example Example 1. General synthetic method.

The compounds of the present invention can be prepared by the methods described below in conjunction with synthetic methods well known to those skilled in the art. The starting materials used herein are either commercially available or can be prepared by conventional methods known in the art (e.g., as disclosed in the standard reference, such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Volumes I-VI ( Published by Wiley-Interscience)). Preferred methods include those set forth below.

Sensitive or reactive groups on any molecule of interest may be required and/or desired to be protected during any of the following synthetic sequences. This can be achieved by means of customary protecting groups, for example as described in the following: T.W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999.

The compounds of the invention or their pharmaceutically acceptable salts can be prepared according to the reaction schemes set forth below. Such methods can be modified or adapted in a manner known to those skilled in the art to achieve the synthesis of other compounds within the scope of the invention. This modification was made to synthesize the exemplary compounds of the invention as described in Examples 2 and 3. Unless otherwise indicated, the substituents in the scheme are as defined above. Separation and purification of the product is accomplished by standard procedures known to chemists familiar with the art.

Those skilled in the art should understand that the various symbols, superscripts, and subscripts used in the schemes, methods, and examples are used to represent and/or reflect the order in which they are incorporated in the embodiments, and are not necessarily The symbol, superscript or subscript in the scope of the appended patent application. The scheme is a representative method that can be used to synthesize the compounds of the invention. It is not intended to limit the scope of the invention in any way.

Synthesis of N-(4-hydroxy-2-methyl-1,3-benzothiazol-5-yl)acetamide:

0.6 g of commercially available 5-azido-2-methyl-1,3-benzothiazole and 5 g of acetic acid were heated to 100 ° C for 20 minutes. Evaporation and column chromatography on the residue gave 0.43 g of N-(4-hydroxy-2-methyl-1,3-benzothiazol-5-yl)acetamide.

Synthesis of 5-amino-2-methyl-1,3-benzothiazol-4-ol:

0.4 g of acetamide was treated with 2 mL of concentrated HCl. Evaporation provided 0.38 g of 5-amino-2-methyl-1,3-benzothiazole-4-ol as the bis-HCl salt.

Synthesis of 7-methyl[1,3]thiazolo[5,4-g][1,3]benzoxazol-2-amine:

To 5 mL of a 3:4 methanol:water solution cooled to 0 °C was added 0.08 mL of bromine followed by 0.12 g of KCN. When the color of bromine disappeared, the cyanogen bromide solution was added to 0.38 g of the amine dihydrochloride in 20 mL of water and 0.252 g of sodium bicarbonate, and the reaction was allowed to stand overnight. The reaction was filtered and the filtrate was taken &lt The residue was dissolved in ethanol and the solution was filtered. The filtrate was concentrated to a residue, which was purified by chromatography to afford 0.14 7-methyl[1,3]thiazolo[5,4-g][1,3]benzoxazole-2-amine.

Example 2. Synthesis of N-(7-methyl[1,3]thiazolo[5,4-g][1,3]benzoxazol-2-yl)thiophene-2-carboxamide Implementation of hydrazine coupling:

To a suspension of 0.15 g of 7-methyl[1,3]thiazolo[5,4-g][1,3]benzoxazol-2-amine in 2.5 mL of anhydrous pyridine was added 0.078 mL of thiophene-2 - Carbonyl chloride. The reaction was stirred at 80 ° C for 5 h and then cooled to room temperature. 4 mL of water was added and the precipitate was filtered off, washed with water and dried to give 0.154 g of N-(7-methyl[1,3]thiazolo[5,4-g][1,3]benzoxazole-2 -yl)thiophene-2-carboxamide.

Example 3. Synthesis of N-[6-(pyrrolidin-1-sulfonyl)-1,3-benzothiazol-2-yl]naphthalene-2-carboxamide

Intermediate 6-(pyrrolidine-1) for the synthesis of N-[6-(pyrrolidin-1-sulfonyl)-1,3-benzothiazol-2-yl]naphthalene-2-carboxamide - sulfinyl)-1,3-benzothiazol-2-amine is synthesized as described below:

A mixture of commercially available 4-(pyrrolidin-1-ylsulfonyl)aniline (1.0 g) and ammonium thiocyanate (1.01 g) was suspended in 25 mL of acetic acid and heated to 90 °C. The mixture was cooled to 15 ° C and liquid bromine (0.22 mL) was added dropwise. The reaction was stirred at room temperature overnight then filtered. The filtrate was concentrated under vacuum and the residue was added to a solution of aqueous sodium hydrogen carbonate and stirred for 1 hour. The precipitate was filtered off, washed with water and ether and dried to give &lt;RTI ID=0.0&gt;&gt;

0.1 g of 6-(pyrrolidin-1-ylsulfonyl)-1,3-benzothiazol-2-amine was dissolved in 2 mL of anhydrous pyridine and 2-naphthoquinone chloride (0.067 g) was added and the mixture was Stir at 80 ° C for 5 h. After cooling to room temperature, the mixture was added to 0.7 mL of water and the precipitate was filtered, washed with water and ether and dried to give &lt;RTI ID=0.0&gt; -benzothiazol-2-yl]naphthalene-2-carboxamide:

Example 4. Antiviral activity and pharmacological properties using structure-activity relationship (SAR) studies

This example illustrates the optimization of compounds against antiviral effects. First, a small set of analog derivatives is used to define the structure class. The active analogs identified in this first stage are then used to define a subset of the structural classes for further optimization (stage 2).

Phase 2 focuses on creating structural diversity and evaluating core variants to extend derivatives. The biological activity of structural derivatives in one or more cell lines or peripheral blood mononuclear cells, including IRF-3 translocation assay, antiviral activity, and cytotoxicity, is tested. Shows improved efficacy and low cells Toxicity-optimized compounds are further characterized by additional measurements of in vitro toxicology and absorption, distribution, metabolism, and elimination (ADME). The mechanism and breadth of its antiviral activity were also studied.

To design analog structures, analysis of drug properties, metabolic instability, and toxic potential of lead compounds. The nature of the drug, such as the Lipinski's Rule, and related physiochemical properties are the main indicators of bioavailability. Structural features indicating metabolic and toxicological possibilities may indicate limited stability, reduced half-life, reactive intermediates or specific toxicity and will therefore be removed.

Highly effective in vitro antiviral activity test compounds against viruses, including HCV 2A, RSV, type 2 DNV and influenza A virus strains. Viral protein and RNA levels were assessed using the assays described herein after drug treatment. The analog design is designed to identify lead compounds with Pimo to Nylon efficacy, which is sufficient to support preclinical development. Lead compounds are described for their in vitro toxicology and ADME properties and other mechanistic studies.

In vitro pharmacological studies are performed to measure the performance of the most promising analogs in one or more of intestinal permeability, metabolic stability, and toxicity. Key in vitro characterization studies may include plasma protein binding; serum, plasma, and whole blood stability in human and model organisms; intestinal permeability; intrinsic clearance; human Ether-à-go-go (hERG) channel inhibition; Genotoxicity.

For each analog, HPLC-based and/or HPLC-mass-based analytical methods were used to assess the concentration of drugs and metabolites in various test systems. While specific assay methods are optimized for each molecule, reverse phase chromatography can be used alone or in combination with quadrupole mass spectrometry to characterize the identity and purity of several lead molecules. Initially, the stability of the drug over time at increasing concentrations in serum, plasma, and whole blood from mammalian species (eg, mice, cynomolgus, and humans) was assessed by HPLC and half-life was determined.

The metabolites are characterized by mass spectrometry. Human plasma protein binding was assessed by segmentation analysis using equilibrium dialysis. For the modeling of intestinal permeability, evaluate the top of the human epithelial cell line TC7 Flow to the side of the substrate. The liver clearance rate was assessed by measuring the rate of disappearance of the parent compound during incubation in human liver microsomes for a subset of the most promising analogs. As described above, specific metabolites can be separated and described.

In vitro toxicology studies were performed to assess the potential cardiac and genotoxicity of the lead analogs. Automated patch clamps were used to evaluate the effect of each compound on hERG channel currents in recombinant Chinese hamster ovary (CHO) cell lines transgenic for human Kvl 1.1 gene. Up to evaluation of the concentration of each compound is less than the maximum of 30 times the solubility limit of the concentration or serum to determine the molecular IC hERG channel of _{50 pairs.} A subset of these compounds was evaluated in a range of concentrations against the ability of the compounds to induce mutations in Salmonella typhimurium strains TA98 and TA100 to reverse or promote micronuclei formation in cultured CHO cells.

Example 5. Biological activity.

This example illustrates a method for identifying compounds that activate an innate immune response, including activation of the RIG-I pathway. Other compounds as described herein can also be evaluated by the methods set forth in this example, and other cell types can also be used.

The Huh 7 cells cultured with the luciferase reporter gene coupled to the RIG-I signaling pathway reaction promoter (IFNβ, ISG56 or ISG54 promoter) were stably transfected and allowed to grow overnight. Compound 1 was then added and the cells were grown for 18-20 hours in the presence of Compound 1. Steady-Glo luciferase substrate (Promega) was added and the luminescence was read on a luminometer (Berthold).

Figure 1A shows luciferase reporters coupled by promoters of IFNβ ("IFNβ-LUC", left), ISG56 ("ISG56-LUC", central) and ISG54 ("ISG54-LUC", right) Dose-dependent induction of the gene to verify Compound 1 of Table 1 as set forth herein. In addition, Compound 1 did not induce a non-specific promoter (β-actin-LUC, Figure 1B).

IRF-3 activation and translocation to the nucleus were determined using immunofluorescence cytochemical analysis. The cultured human HeLa cells were treated with an increasing amount of compound diluted in the medium or an equal amount of DMSO for 20 hours. Positive control wells were infected with 100 HA/mL Sendai virus for an equivalent period of time. Specific for IRF-3 rabbit serum conjugated to much strain and DyLight ^® (Pierce Biotechnology Company, Rockford, IL) 488 of the secondary antibody detection IRF-3.

Immunofluorescence cytochemical analysis was used to determine NFκB activation. The innate immune response also depends on the activation of the NFκB transcription factor. The cultured human HeLa cells were treated with an increasing amount of compound diluted in the medium or an equal amount of DMSO for 20 hours. Positive control wells were infected with 100 HA/mL Sendai virus for an equivalent period of time. NFκB was detected using a single mouse antibody specific for the p65 subunit of NFκB and a secondary antibody conjugated to DyLight 488.

IRF-3 NFκB performed immunofluorescent of the quantization set forth herein and the following analysis: using ArrayScan ^® instrument and software (the Cellomics) containing 96 scans and quantizes the compound treated and cultured for IRF-3 or NFKB of staining of human cells Orifice plate. Activation of transcription factors is evidenced by increased nuclear intensity or nuclear-cytoplasmic differences for normalization of cytoplasmic intensity. Compound 1 showed a dose-dependent increase in nuclear-cytoplasmic differences between IRF-3 (Figure 1C) and NFKB (Figure 1D).

Analysis of innate immune gene expression was performed in cell types including HeLa cells, PH5CH8 cells, and HUVEC primary cells. Gene expression can be similarly analyzed in a variety of cell types, including: primary blood mononuclear cells, human macrophages, THP-1 cells, Huh 7 cells, A549 cells, MRC5 cells, rat spleen cells, rat thymus Cells, mouse macrophages, mouse spleen cells, and mouse thymocytes. The performance of other genes of interest can be analyzed as described herein.

The cultured HeLa cells were treated with 20 μM, 10 μM, 5 μM compound or DMSO control and incubated for up to 24 hours. The cultured PH5CH8 cells were treated with 10 μM, 5 μM, 1 μM or DMSO control and incubated for up to 24 hours. That the primary HUVEC cells were thawed and to 2.4 × 10 ⁴ cells / well were seeded in 6-well plates and grown to 80% confluence, usually cultured for 5 days and replaced with fresh medium every 48 hours. 10 μM, 1 μM compound or DMSO control was added and incubated for up to 24 hours. Gene expression was analyzed as described below.

Cells were harvested and RNA was isolated using a QIAshredder column and RNeasy mini set (Qiagen) according to the manufacturer's instructions. Reverse transcription was performed and cDNA templates were used for quantitative real-time PCR. PCR reactions were performed using commercially validated TaqMan gene performance assays (Applied Biosystems/Life Technologies) according to the manufacturer's instructions. The degree of gene expression was measured using a relative performance analysis (ΔΔCt).

Figures 2A-2C show the gene expression induced by compounds 1 and 2 of Table 1. Figure 2A shows that IFIT cells were treated with 10 μM of Compound 1 (grey; OAS1 only) or 10 μM of Compound 2 (black; showing both IFIT2 and OAS1) after IFIT2 (left) and OAS1 (right) over time (from 4 hours to 24) Hour) The degree of gene expression. Figure 2B shows the degree of gene expression of IFIT2 in PH5CH8 cells (solid color bars) and HeLa cells (black check bars) treated with 10 μM of Compound 1 (CPD 1) or Compound 2 (CPD 2). 2C shows the degree of gene expression of IFIT2 (left), OAS1 (central), and MxA (right) in primary HUVEC cells treated with 1 μM Compound 1 (CPD 1) or 1 μM Compound 2 (CPD 2).

Figures 3A-3B show the gene expression induced by Compound 3 and Compound 7 of Table 1. Figure 3A shows the expression of the IFIT2 gene induced by 5 μM Compound 3 or Compound 7. Figure 3B shows Compound 3 induced congenital immune gene expression in mouse macrophage cells.

Example 6. Ex vivo immunostimulatory activity of Compound 1

The activity of Compound 1 of Table 1 in primary immune cells was analyzed to determine if Compound 1 stimulates the immune response. The cultured human primary dendritic cells were treated with 0 μM, 1 μM or 10 μM of Compound 1 for 24 hours. The supernatant above the treated wells was separated and tested for interleukin protein content. Cytokines are detected using a specific antibody conjugated to magnetic beads and a secondary antibody that reacts with streptavidin/Phycoerythrin to generate a fluorescent signal. Use Magpix ^® (Luminex Corporation) detecting apparatus and quantify bound beads, but it can be used similar techniques known in the art to measure the fluorescent protein production (e.g., ELISA).

Figure 4 shows the induction of chemokines IL-8, MCP-1, MIP-1α and MIP-1β by dendritic cells treated with Compound 1 of Table 1 (concentration expressed in μM). LPS is shown to be a positive control inducer of chemokine expression.

Other cells that can be quantified by cytokines include, for example, human peripheral blood mononuclear cells, human macrophages, mouse macrophages, mouse spleen cells, rat thymocytes, and rat spleen cells.

Example 7. In vitro antiviral activity

To further describe the breadth of antiviral activity of optimized molecules, cell culture infection models were used to analyze different strains, including influenza virus, HCV, DNV, RSV, and WNV, which are emerging public health issues. Studies included treating cells with compounds 2-24 hours prior to infection or treating cells up to 8 hours after infection. Viral production and cellular ISG performance were evaluated over a period of time to analyze the antiviral effects of representative compounds from the class of lead structures. A known antiviral treatment including IFNβ was used as a positive control.

Viral production is measured by lesion formation or plaque assay. Viral RNA and cellular ISG performance were measured by qPCR and immunoblot analysis in parallel experiments. These assays were designed to verify the signaling effects of compounds during viral infection and to evaluate the role of the compounds in direct congenital immune antiviral programs against various viral strains and in the context of viral countermeasures. Detailed dose-response analysis of each compound was performed in each viral infection system to determine the effectiveness of both 50% (IC50) and 90% (IC90) inhibition of virus production compared to control cells for both pre- and post-treatment infection models. dose.

The compounds of the invention were tested using an in vitro model against the following viruses, including: hepatitis B virus (HBV), HCV H77 (genotype 1a), HVV JFH1 (genotype 2a), influenza A/PR/8/34 ( H1N1 mouse adaptive virus), influenza A/WSN/33 (H1N1 mouse adaptive neurotoxic virus), influenza A/TX/36/91 (H1N1 circulating virus), influenza A/Udorn/ 72 (H3N2), WNV TX02 (lineage 1), WNV MAD78 (lineage 2), RSV, human coronavirus OC43 (SARS-like pathogen) and type 2 DNV.

The antiviral activity of the exemplary compounds of the present invention is demonstrated in Examples 8 to 11 below.

Example 8. In vitro activity against respiratory syncytosis virus

HeLa cells were seeded at 4 x 10 ⁵ cells/well in a 6-well plate the day before. The next day, the medium was changed to RSV in a medium containing no FBS with an MOI of 0.1. Viral binding occurred at 37 ° C for 2 hours. After 2 hours, the cells were washed with warm complete medium and replaced with medium containing different concentrations of drug or DMSO control at 10 μM, 5 μM, 1 μM. The cells were placed in a 37 ° C incubator for 48 hours.

For virus detection and titer determination, HeLa cells were seeded at 8 x 10 ³ cells/well in 96-well plates 24 h before virus supernatant collection. After a 48 hour incubation period, virus supernatants from infected plates were harvested and used to infect the cells with a 1/10 final dilution. The cells were placed in a 37 ° C incubator for 24 hours.

24 hours after infection, the cells were washed twice with PBS and fixed with a methanol/acetone solution. After fixation, the cells were washed twice with PBS and replaced with blocking buffer (10% horse serum, 1 g/mL BSA and 0.1% Triton-100X in PBS) and held for 1 hour. The blocking buffer was exchanged for binding buffer containing 1/2000 dilution of primary antibody and maintained at room temperature for 2 hours. The primary antibody is a mouse monoclonal antibody that is resistant to RSV. The cells were washed twice with PBS and replaced with a 1/3000 dilution of Alexa Fluor-488 goat anti-mouse secondary antibody and Hoechst nuclear stain binding buffer at room temperature. Hold for 1 hour. The cells were washed twice with PBS and PBS was added to all wells. The 96-well plate was sealed, and the fluorescence activity associated with viral infectivity was determined by immunofluorescence analysis using an Array Scan instrument (Thermo-Fischer).

Treatment with a compound can be carried out prior to infection. In a variation of this method, the compound is added at different time points prior to viral infection. Virus detection and potency assays were performed as described.

Figure 5 shows the results of an experiment performed using the protocol of Example 8, which demonstrates that the selected compounds that are resistant to the antiviral activity of RSV have antiviral activity. +++ = inhibition of infection greater than 70%, ++ = inhibition greater than 50%, + = inhibition greater than 30%, - = inhibition less than 30%.

Example 9. In vitro activity against influenza virus.

Influenza A/Udorn/72 infection of H292 cells. Compound 2 in 2 μM of DMSO at a final concentration of 0.5% was treated with 2 x 10 ⁶ H292 cells in RPMI 1640 + 10% FCS for 6 hours. The medium containing the compound was withdrawn and replaced with 1×MEM containing A/Udorn/72 having an MOI of 0.1, and placed at 37 ° C in a CO ₂ incubator. Two hours after infection, the virus-containing medium was withdrawn and replaced with 1×MEM containing 1 μg/mL TPCK-treated trypsin, 2 μM compound 2, and 0.5% DMSO. The cells were placed in a 37 ° C CO ₂ incubator for 18 hours. Twenty hours after infection, viral supernatants were collected and titer of MDCK cells was determined.

Influenza A/Udorn/72 infection of HEK293 cells. In the 1 × MEM for A / Udorn / 72 were infected at MOI 0.2 5 × 10 ⁵ th HEK293 cells. Two hours after infection, the virus-containing medium was withdrawn and replaced with 1×MEM containing 1 μg/mL TPCK-treated trypsin, 10 μM compound 2, and 0.5% DMSO. The cells were returned to a 37 ° C CO ₂ incubator for 18 hours. Twenty hours after infection, viral supernatants were collected and titer of MDCK cells was determined.

Potency in MDCK cells. 10 μL of the infected supernatant was added to 2 × 10 ⁶ MDCK cells in the presence of 2 μg/mL TPCK-trypsin and placed in a 37 ° C CO ₂ incubator. After 8 hours, the supernatant was removed and the cells were fixed and stained with FITC-conjugated antibodies specific for influenza NP protein. The number of lesions was quantified using ArrayScan instruments and software (Cellomics).

The protocol of Example 9 can be practiced as described to assess the antiviral activity of the exemplified compounds. Figure 6 shows the antiviral activity of the example compound against the influenza A virus Udorn/72 Sex. Treatment of HEK293 cells with increasing concentrations of Compound 1, Compound 7, Compound 9, and Compound 10 of Table 1 caused dose-dependent inhibition of viral infection (shown as % untreated negative control). The calculated IC50 value is displayed. Table 2 shows the calculated IC50 values for the selected compounds of Table 1.

Example 10 is resistant to the in vitro activity of dengue virus.

The cultured human Huh 7 cells were seeded at a density of 4 × 10 ⁵ cells/well in 6-well tissue culture plates and grown for 24 hours. The cells were infected with a type 2 DNV strain at a multiplicity of infection (MOI) of 0.1 for 2 hours and then removed. Compound dilutions were prepared in 0.5% DMSO and used to treat cells at a final compound concentration ranging from 0.001 [mu]M/well to 10 [mu]M/well. Vehicle control wells treated with 0.5% DMSO were compared to drug treated cells. Let the copy continue for 48 hours. The viral supernatant was harvested and used to infect a new licensed cell monolayer, such as Vero cells seeded in 96-well plates at 8 x 10 ³ cells/well 24 hr prior to collection of viral supernatant.

The newly infected cells are incubated for 24 hours and used for immunization with viral proteins Fluorescence staining measures the amount of infectious virus in the initial supernatant. Cells were fixed in ice-cold 1:1 methanol and acetone solutions and stained for DNV fusion protein. A single mouse monoclonal antibody (Millipore) resistant to DNV fusion protein diluted 1:2000 was used. DNV proteins and nuclei were detected at 1:3000 using a secondary goat anti-mouse antibody conjugated to Alexa Fluor 488 dye (Invitrogen) and Hoescht dye (nuclear stain). After incubation of the secondary antibodies, the monolayers were washed and then placed in 100 [mu]L PBS for imaging and quantified using a Cellomics ArrayScan HCS instrument.

Figure 7 shows the antiviral activity of Compound 1 and Compound 20 of Table 1 against type 2 dengue virus (DNV). Treatment with an increasing amount of compound showed a dose-dependent reduction in viral infection.

Figure 8 shows the antiviral activity of exemplary compounds against type 2 dengue virus. Treatment of Huh 7 cells with increasing concentrations of Compound 8, Compound 3, Compound 5, Compound 6, Compound 7, Compound 9, and Compound 10 of Table 1 resulted in dose-dependent inhibition of viral infection (shown as untreated negative control) %). The calculated IC50 value is displayed.

Table 3 shows the calculated IC50 values for selected compounds against type 2 dengue virus (DV2) and/or type 4 dengue virus (DV4).

Example 11. In vitro activity against human coronavirus.

MRC5 cells were seeded in 6-well plates the day before and allowed to grow for 24 hours. Cells were infected with human coronavirus OC43 (HCoV-OC43) for 2 hours and then removed. Compound dilutions were prepared in 0.5% DMSO and used to treat cells at a final compound concentration ranging from 0.001 [mu]M/well to 10 [mu]M/well. Vehicle control wells treated with 0.5% DMSO were compared to drug treated cells. Let the copy continue for 5 days. The viral supernatant was harvested and used to infect a new licensed cell monolayer, such as Huh 7 cells seeded in 96-well plates 24 hours prior to collection of the viral supernatant (i.e., 4 days post infection).

The newly infected cells were incubated for 48 hours and used to measure the amount of infectious virus in the initial supernatant by immunofluorescence staining of viral proteins. Cells were fixed in ice-cold 1:1 methanol and acetone solutions and stained for HCoV-OC43 nuclear protein. A mouse monoclonal antibody (Millipore) resistant to HCoV-OC43 nucleoprotein was used at a dilution of 1:1000. A second goat anti-mouse antibody conjugated to Alexa Fluor 488 dye (Invitrogen) and Hoescht dye (nuclear stain) was used at 1:3000 to detect OC43 protein and nucleus. After incubation of the secondary antibodies, the monolayers were washed and then placed in 100 [mu]L PBS for imaging and quantified using a Cellomics ArrayScan HCS instrument.

Figure 9 shows the antiviral activity of exemplary compounds against human coronavirus OC43. Treatment with increasing concentrations of Compound 1, Compound 5, Compound 6, and Compound 7 of Table 1 caused dose-dependent inhibition of viral infection (shown as % untreated negative control). The calculated IC50 value is displayed.

Table 4 shows the calculated IC50 values for selected compounds against human coronavirus OC43.

Example 12. In vivo pharmacokinetic and toxicological properties of the compound.

The in vivo pharmacokinetic (PK) profile and tolerance/toxicity of the compounds described herein were evaluated to further describe their in vivo antiviral activity.

The concentration of each compound in mouse plasma was measured using a reverse phase HPLC-MS/MS detection method. Prior to PK profiling, initial oral and intravenous formulations for each compound were developed using a limited formulation of components that focused primarily on maximum aqueous solubility and stability under small storage conditions. The performance of the formulation can be measured using any analytical method known in the art. Formulations were developed for each compound according to a three-layer strategy: Layer 1: pH (pH 3 to 9), buffer and osmotic pressure regulation

▪ Layer 2: Add ethanol (<10%), propylene glycol (<40%) or polyethylene glycol (PEG) 300 or 400 (<60%) cosolvent to enhance solubility

▪ Layer 3: Add N - N -dimethylacetamide (DMA, <30%), N -methyl-2-pyrrolidone (NMP, <20%) and/or dimethyl hydrazine (DMSO) , <20%) cosolvent or cyclodextrin (<40%) (if needed) to further improve solubility.

Example 13. In vivo antiviral activity of a compound.

A preliminary mouse PK study was performed on compounds exhibiting sufficient performance in in vitro antiviral, mechanistic, ADME and toxicology studies. After overnight fasting, each compound was administered to the animals as a single dose by oral gavage (<10 ml/kg) or intravenous bolus (<5 ml/kg). Each of the administration groups was administered to a plurality of animals such that 3 animals were sampled at each time point. Blood samples were collected by retro-orbital sinus before administration and at 5 minutes, 15 minutes and 30 minutes, and at 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. The drug concentration was measured according to a previously developed bioanalytical method. The PK parameters were evaluated using the WinNonlin software.

Based on the performance in the exploratory PK study, the initial tolerance and toxicity of the compounds in mice was further evaluated prior to characterization in the antiviral model. Tolerance studies were performed in two phases: the initial dose escalation phase (up to 5 doses, each separated by a 5-day washout period) to determine the maximum tolerated dose (MTD; Stage 1), followed by daily dosing 7 times of MTD to assess acute toxicity (stage 2). All doses were administered by oral gavage. In the example experiment, 5 animals per sex were placed in Phase 1 for study, while in Phase 2 each animal was 15 animals per sex. Study endpoints included MTD measurements, physical examinations, clinical observations, hematology, serum chemistry, and animal weight. Overall pathology was performed on all animals (whether or not death was found), and euthanasia was performed in extreme cases or when the experiment was intended to end. The main exploration of the nature of the toxicology research department is intended to identify early toxicological endpoints and to promote the selection of lead candidates for antiviral animal models.

Example methods for accomplishing the PK and tolerance studies set forth above are shown in Table 5. Such methods can be modified and/or adapted (e.g., different routes of administration) to more accurately measure the pharmacological properties of the compound.

Figure 10 shows the results of an exploratory PK study. Administration of Compound 3 of Table 1 via the oral (PO) or intravenous (IV) route allowed the amount of compound to be detected in serum samples obtained up to 250 minutes after treatment (Fig. 10A). At 4 hours after treatment of Compound 3 and Compound 7 of Table 1, compounds were detected in lung tissue (Fig. 10B).

Exemplary compounds of the invention that exhibit desirable PK properties, tolerability, antiviral efficacy, and/or innate immune activation activity are selected for further evaluation in a preclinical mouse infection model.

The effective dose (EC) for each compound for 50% and 90% serum viral load suppression after challenge with standard viruses (eg, 100 pfu of WNV-TX or 1,000 pfu of influenza virus) was included in the design of these experiments. Determination of ₅₀ and EC ₉₀ ). Viral quantification in serum and/or target tissues is determined by established analytical methods including: plaque assay, TCID ₅₀ analysis, lesion formation analysis, viral protein quantification (eg, by HA analysis or BCA analysis), viral RNA Quantification (for example by means of qPCR) and/or antigen quantification (for example by means of ELISA).

To study viral challenge dose amount of at least 2 (including the EC ₅₀ was determined and EC ₉₀₎ effect the test compounds to assess which limits viral pathogens, viral replication and spread of the virus ability. Monitoring the incidence of mice in combination with an attack dose (eg, 10 pfu to 1,000 pfu virus) alone or with a compound treated at 12 hours prior to infection or 24 hours after infection and continuing daily for the plasma half-life determination of the drug mortality rate. Compound dose response analysis and infection time course studies were also performed to assess the efficacy of the compounds against 1) limiting serum viral load, 2) limiting viral replication and spread in target organs, and 3) protecting against viral pathogenicity.

Table 6 describes the effective doses defining the in vivo drugs and the established mouse virus infection model. Type of study, but this list is not intended to be complete and can test the efficacy of a compound against any viral infection in any mouse model.

Mouse WNV model. The efficacy of a compound against WNV can be analyzed after subcutaneous or intracranial (neurological invasion) infection of the virus. Compounds were administered daily by oral gavage or IP administration in 2 doses plus placebo control throughout the infection. Animals were assessed at the end of the study, including daily clinical observations, mortality, body weight, and body temperature. Viral titers in serum, lymph nodes, spleen and/or brain are measured. The gene and interleukin expression at each time point during infection in the compound treated animals relative to the control animals can be analyzed.

Mouse influenza model. Viral infection was achieved by instilling influenza virus strains A/WSN/33 and A/Udorn/72 intranasally or intra-organically. These influenza virus strains have two different subtypes (H1N1 and H3N2) and exhibit different pathogenic properties and clinical manifestations in C57B1/6 mice. Throughout the infection process ( 2 weeks) Compounds were administered daily by oral gavage or IP administration in 2 doses plus placebo control. Animals were assessed at the end of the study, including daily clinical observations, mortality, body weight, and body temperature. Viral titers in serum, heart, lung, kidney, liver, and/or brain are measured. The gene and interleukin expression at each time point during infection in the compound treated animals relative to the control animals can be analyzed.

Mouse RSV model. Viral infection is achieved by instilling RSV A2 long strain intranasally or intra-organically in a dose that does not cause cytopathic effects. Daily administration of the compound by oral gavage or IP administration in 2 doses or placebo control 3 weeks. Animals were assessed at the end of the study, including daily clinical observations, mortality, body weight, and body temperature. The virus titer in serum, blood and/or lung is measured. Analyze gene and interleukin performance and increase the number of immune cell populations.

Mouse DNV model. Viral infection was achieved by intraperitoneal injection of a type 2 DNV strain. Compounds were administered daily by oral gavage or IP administration in 2 doses plus placebo control throughout the infection. Animals were assessed at the end of the study, including daily clinical observations, mortality, body weight, and body temperature. Viral titers in serum, blood, heart, lung, kidney, liver, and/or brain are measured. The gene and interleukin expression at each time point during infection in the compound treated animals relative to the control animals can be analyzed.

Mouse Hepatitis Virus Type 1 (MHV-1) Coronavirus Model. Viral infection was achieved by non-surgical intranasal instillation of MHV-1. Throughout the infection process ( One week) Compounds were administered daily by oral gavage or IP administration in two doses plus a placebo control group. Animals were assessed at the end of the study, including daily clinical observations, mortality, body weight, and body temperature. Viral titers in serum, heart, lung, kidney, liver, and/or brain are measured. The gene and interleukin expression at each time point during infection in the compound treated animals relative to the control animals can be analyzed.

Figure 11 shows a study performed using the mouse type 1 hepatitis virus (MHV-1) coronavirus model. Treatment with Compound 3 of Table 1 resulted in a reduction in pathological symptoms (including weight loss) and an increase in survival (B) after lethal challenge with MHV-1. (C) The virus in the lungs of the animals treated with Compound 3 was reduced.

Table 7 illustrates the antiviral activity of the exemplified compounds.

Example 14. In vivo adjuvant activity

To describe the breadth of adjuvant activity of the compounds of the invention, vaccination and vaccination plus protected animal models are used. Studies included priming of animals (including rats and mice), either alone or in combination with antigens, and then evaluating the adjuvant effect.

Adjuvant effects were measured by analysis of modified, enhanced immune body fluids and cellular responses. Collecting blood serum and determining antibody class (IgM, IgG, IgA or IgE) and/or isotype (including IgG antibodies) over time in vaccination and/or boosting The relative concentrations of IgG1, IgG2a, IgG2b, IgG2c, and IgG3) were used to evaluate the humoral response. In addition, the affinity (avidinity and avidity) of the produced antibodies was also measured. In the case where the vaccine preparation comprises a combination of a compound and an antigen, the neutralizing activity of the produced antibody is also determined.

By means of established methods in the field (including stimulation of peripheral blood mononuclear cells, lymph nodes, spleen cells or other secondary lymphoid organs with antigens, and measuring the interleukin or chemotaxis in the supernatant for some time thereafter) The production of a gene) measures the induction of a cell-mediated immune response by a compound. The measured interleukins include Th1-type interleukins (including IFN γ and TNF α), Th2-type interleukins (including IL-4, IL-10, IL-5, and IL-13) and Th17 interleukins. (including IL-17, IL-21 and IL-23). Chemo-inducible chemokines, including RANTES, IP-10, MIP1a, MIP1b, and IL-8, were also measured. Specific production of intercellular T cell antigens can also be measured by intracellular interleukin staining and flow cytometry using fluorescently labeled specific antibodies or by ELISPOT. Study CD4+ and CD8+ T cell populations.

Immunophenotyping of activated surface markers was also performed by flow cytometry to determine the amount of adjuvant activity at the cell level. CD8 T cell antigen-specific responses are also assessed by intracellular intercellular staining of proteins, cell surface marker expression or proliferation assays including thymidine incorporation.

These experiments were designed to verify the adjuvant activity of the compounds in different combinations of prime-boost regimens and to evaluate how the effects of the compounds induced against the innate immune antiviral program form adaptive immune responses to antigens produced in vaccine formulations. .

Detailed immunoreactivity analysis of each of the compounds as set forth above is performed using each of the selected antigens to determine the immunological association with the particular antigen and compound formulation. These results direct protection studies in which an animal vaccinated and boosted with a combination of the selected optimized compound and the desired antigen formulation from the selected infectious agent is later attacked with an infectious agent known to cause the disease or death of the animal. . Protection by vaccination is usually measured by monitoring clinical symptoms and survival.

Example 15. Compound 12 of Table 1 is resistant to the antiviral activity of Ebola virus.

Compound 12 of Table 1 was tested against the in vitro potency of Ebola virus (EBOV). As shown in Figure 12, Compound 12 showed greater than 2 log reduction in EBOC titers in vitro. The control titer (pfu/mL) exceeded 5, while the test titer using Compound 12 was less than 3.5.

Example 16. Antiviral effect of Compound 8 of Table 1.

Figure 13 shows the dose-response activity of Compound 8 of Table 1 against DENV-2 (expressed in FFU/ml).

Illustrative embodiment

A compound represented by the formula: Wherein R ⁴ is R ^d , SO ₂ R ^d , C(=O)R ^d , NH C(=O)R ^d , R ^e , OR ^c or CF ₃ , wherein R ^c is H or C ₁ -C ₁₀ hydrocarbyl And R ^d is a substituted heterocyclic ring, an unsubstituted heterocyclic ring or an unsubstituted carbocyclic ring, and R ^e is a substituted heteroaryl group or a substituted phenyl group; and n is 1 or 2.

2. A compound as in Example 1 which is represented by the formula: Wherein R ⁴ is: (i) C(=O)R ^d and R ^d is pyrrolidinyl, (ii) SO ₂ R ^d and R ^d is hexahydropyridyl, (iii) NHC(=O)R ^d And R ^d is phenyl or furyl, (iv) imidazolyl, or (v) thiazolyl.

3. A compound as in Example 1 which is represented by the formula: Wherein X is NH or O.

4. A compound according to embodiment 1, wherein R ⁴ is CF ₃ , OR ^c or a phenyl group substituted with at least one OCH ₃ group.

5. The compound of claim 1 which is represented by the formula:

6. A compound represented by the formula: Wherein L is NR ² , O, S, C(=O)N, CR ² R ³ CR ² R ³ , CR ² R ³ NR ² , CR ⁴ =CR ⁴ , CR ² R ³ O, CR ² R ³ S NR ² CR ² R ³ , NR ² C(=O), NS(O) _t , OCR ² R ³ , SCR ² R ³ ; V system (CR ² R ³ ) _u , C(=O)CR ² R ³ , CR ² R ³ O, CR ² R ³ OCR ² R ³ , CR ⁴ =CR ⁴ , C≡C, C(=NR ² ) or C(=O); Q series NR ² , O, S(O _t or bond; t = 0, 1, 2; u = 0 to 3; wherein the dotted line indicates the presence or absence of a bond; R ¹ is R ^a , OR ² or NR ² R ³ ; each R ^{a is} independently H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² and R ³ are each independently R ^a , C(=O)R ^a , SO ₂ R ^a Or R ² and R ³ form an optionally substituted carbocyclic, heterocarbocyclic, aryl or heteroaryl ring; each R ^{4 is} independently R ² , OR ^a , C(=O)R ^a , C (=O)NR ² R ³ , NR ² R ³ , NR ^b (=O)R ^a , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , SO ₂ NR ² R ³ , NCOR ^a , halogen , trihalomethyl, CN, S = O, a nitro group, or two R ⁴ groups optionally form of substituted carbocyclic, heteroaryl carbocyclic, aryl or heteroaryl ring; W is and X are each independently Tied ^{N, NR a, NR 5,} O, S, CR 2 R 4 or CR ^4; R ⁵ based ^{R a, C (= O)} R a, SO 2 R a or absent; Y ^1, Y ^2, Y ³ and Y ⁴ are each independently CR ⁴ or N; and NR ² R ³ may form an optionally substituted heterocyclic or heteroaryl ring including pyrrolidine, hexahydropyridine, morpholine and hexahydropyrazine.

7. A compound as in Example 6, which has a structure represented by Formula 1A or 1C Wherein in any of Formula 1A and Formula 1C, R ¹ is R ^a , OR ² or NR ² R ³ ; each R ^{a is} independently H, optionally substituted hydrocarbyl, optionally substituted And optionally substituted heteroaryl; R ² and R ³ are each independently R ^a , C(=O)R ^a or SO ₂ R ^a ; each R ^{4 is} independently R ² , OR ^a , NR ² R ³ , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , NCOR ^a , C(=O)R ^a , CONR ² R ³ , halogen, trihalomethyl, CN, S=O or nitrate a group; V is CR ² R ³ , C(=O), C(=O)CR ² R ³ or C(=N)R ² ; and W is O or S.

8. A compound as in Example 6, which has the structure represented by Formula 1B Wherein R ¹ is R ^a , OR ² or NR ² R ³ ; each R ^{a is} independently H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² And R ³ are each independently R ^a , C(=O)R ^a or SO ₂ R ^a ; each R ^{4 is} independently R ² , OR ^a , NR ² R ³ , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , NCOR ^a , C(=O)R ^a , CONR ² R ³ , halogen, trihalomethyl, CN, S=O or nitro; R ⁶ H or CH ₃ , V system CR ² R ³ , C(=O), C(=O)CR ² R ³ or C=NR ² ; and W is O or S.

Compound of Example 7 8 or 9. The embodiment wherein R ⁴ lines H; and V lines C = O.

The compound of any one of embodiments 7, 8 or 9, wherein R ¹ is optionally substituted phenyl or optionally substituted naphthyl.

The compound of any one of embodiments 6 to 10, wherein W is S such that X is N.

The compound of any one of embodiments 6 to 10, wherein W is O and X is N.

13. A compound according to any one of embodiments 6 to 11 which is represented by the formula: Wherein R ¹ is a phenyl group substituted with at least one halogen, a phenyl group substituted with NR ² R ³ , a phenyl group substituted with SO ₂ NR ² R ³ , CR ² R ³ ORd, an unsubstituted naphthyl group, via O _{^{(CR 2 R 3) n R}} d, NR a (CR 2 R 3) n R d, NR a (CR 2 R 3) n NR 2 R 3 substituent of the naphthyl groups, including phenyl and pyridyl ring of two a structure, or a two-membered ring structure comprising a phenyl group and a dioxolanyl group; each R ^{a is} independently H or an optionally substituted hydrocarbyl group (C ₁ -C ₁₀ ); R ² and R ³ are each independently R ^a , COR ^a , (CH 2 ) _n O or SO ₂ R ^a ; each R ^{4 is} independently R ^a R ^d phenyl or morpholinyl R ⁵ H or CH ₃ ; R ⁶ H or CH ₃ And wherein n is 1, 2, 3 or 4.

14. A compound of embodiment 13 which is represented by the formula:

15. A compound according to any one of embodiments 5 to 9 and 11 which is represented by: Wherein R ¹ is phenyl substituted with at least one halogen, phenyl substituted with NR ² R ³ , phenyl substituted with SO ₂ R ^d , naphthyl optionally substituted by O(CR ² R ³ ) _n R ^d Or unsubstituted naphthyl, each R ^{a is} independently H or optionally substituted C ₁ -C ₁₀ hydrocarbyl; R ² , R ³ and each R ^{4 are} independently R ^a , R ^d as appropriate Substituted phenyl or optionally substituted morpholinyl; R ⁵ is H or CH ₃ ; R ⁶ is H or CH ₃ , and wherein n is 1, 2, 3 or 4.

16. A compound of embodiment 15 which is represented by the formula:

A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 16.

18. A method of treating a viral infection in an individual comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of Example 17, thereby treating the viral infection in the individual.

19. A method of preventing viral infection in an individual comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition of embodiment 17.

20. The method of embodiment 18 or embodiment 19, wherein the viral infection is caused by a virus of one or more of the following families: the arenavirus family, the arteritis virus genus, the astrovirus family, the ribonucleic acid virus Branch, brome mosaic virus, Bunia virus, calicivirus, monastery virus, cowpea mosaic virus, coronavirus, cystic phage, filamentous genus, flavivirus, curved virus Branch, hepatic deoxyribonucleic acid, hepatitis virus, herpesvirus, smooth phage, yellow virus, medium virus, single-stranded anti-virus, mosaic virus, nido virus, wild virus Branch, positive mucus virus, papillomavirus, paramyxoviridae, small ribonucleic acid, small ribonucleic acid, picornavirus, potato Y virus, reoviridae, anti The family of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the virus.

21. The method of embodiment 18 or embodiment 19, wherein the viral infection is caused by: Alf virus, Banzi virus, bovine diarrhea virus, TB virus, dengue virus (DNV), hepatitis B virus ( HBV), hepatitis C virus (HCV), human cytomegalovirus (hCMV), human immunodeficiency virus (HIV), leis virus, influenza virus (including poultry and pig isolates), rhinovirus, promise Walker virus, adenovirus, Japanese encephalitis virus, Kokobara virus, Kuching virus, Kosano forest disease virus, sheep jumping disease virus, measles virus, MERS-coronavirus (MERS), interstitial pneumonia virus, embedded Any of the virus, Murray Valley encephalitis virus, parainfluenza virus, poliovirus, Poisen virus, respiratory syncytial virus (RSV), Rocio virus, SARS-Coronavirus (SARS) ), St. Louis encephalitis virus, tick-borne encephalitis virus, West Nile virus (WNV), Ebola virus, Nipah virus, Risa virus, Takaripi virus, Junin virus and yellow fever virus.

22. A pharmaceutical composition according to embodiment 17 for use in therapy.

23. The pharmaceutical composition for use in embodiment 22, wherein the pharmaceutical composition is administered as an adjuvant to a prophylactic or therapeutic vaccine.

A method of modulating an innate immune response in a eukaryotic cell, comprising administering to the cell a compound according to any one of embodiments 1 to 16.

25. The method of embodiment 24, wherein the cell line is in vivo.

26. The method of embodiment 25, wherein the cell line is in vitro.

27. A method of treating a viral infection in an individual comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition having the structure: And wherein the viral infection is caused by the Ebola virus.

It will be appreciated by those skilled in the art that each embodiment disclosed herein may comprise, consist essentially of or consist of elements, steps, components or components. Therefore, the term "include or includes" shall be interpreted as a statement: "comprising, consisting of or consisting essentially of". As used herein, the term "comprise" or "comprises" is intended to include, but is not limited to, and includes elements, steps, components, or components that are not specified, even if such quantities are numerous. The transitional phrase "consisting of" excludes any element, step, ingredient or component not specified. The transitional phrase "consisting essentially of" limits the scope of the embodiments to the specified elements, steps, components or components and those which do not substantially affect the embodiments. As used herein, a material effect will result in a viral infection in a treated individual of the disclosed compound or composition; a reduction in the individual or analyzed viral protein; a statistically significant reduction in the ability of an individual or analyzed viral RNA or a reduction in virus in cell culture. reduce.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., molecular weight), reaction conditions, and the like, used in the specification and claims are to be construed as being modified by the term "about". Accordingly, the numerical parameters set forth in the specification and the appended claims are to be construed as an approxi At the very least, and not as an attempt to limit the application of the &lt;RTI ID=0.0&gt; In the event that further elaboration is required, the term "about" when used in conjunction with the specified value or range, has the meaning that the person skilled in the art is reasonably attributed to it, that is, the stated value or range is slightly more or slightly less, Within the following ranges: ±20% of the specified value; ±19% of the specified value; ±18% of the specified value; ±17% of the specified value; ±16% of the specified value; ±15% of the specified value; ±14% of Specified value; ±13% of the specified value; ±12% of the specified value; ±11% of the specified value; ±10% of the specified value; ±9% of the specified value; ±8% of the specified value; ±7% of the provisions Value; ± 6% of the specified value; ± 5% Specified value; ±4% of the specified value; ±3% of the specified value; ±2% of the specified value; or ±1% of the specified value.

Notwithstanding that the numerical ranges and parameters of the broad scope of the present invention are approximations, the stated values are reported as precisely as possible in the particular examples. However, any numerical value inherently contains an inevitable error necessarily resulting from the standard deviation present in its respective test.

The terms "a", "an", "the", and the like are used in the context of the context of the present invention, particularly in the context of the claims below, unless otherwise indicated herein. It should be understood to cover both singular and plural. The numerical ranges set forth herein are intended only as a shorthand method of individually referring to individual values within the range. Unless otherwise stated herein, individual values are generally incorporated into the specification as if they were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples or exemplary language (such as "such as") is intended to be illustrative only and not to limit the scope of the invention. Nothing in the specification should be construed as indicating that any non-claimed elements are essential to the practice of the invention.

The grouping of alternative elements or embodiments of the invention disclosed herein is not to be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is contemplated that one or more members of the group may be included in the group or one or more members of the group may be deleted from the group for reasons of convenience and/or patentability. When any such inclusion or deletion is made, the specification is deemed to contain the modified group, thereby achieving a written description of all Markush groups used in the accompanying claims.

Certain embodiments of the invention have been described herein, including the best mode known to the inventors of the invention. Of course, those skilled in the art will be aware of the variations of the described embodiments as they are described. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend that the invention may be practiced otherwise than as specifically described herein. Practice. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the appended claims. In addition, any combination of the above-described elements in all possible variations thereof is encompassed by the present invention unless otherwise stated herein or clearly contradicted by the context.

Publications, patents, and/or patent applications (collectively, "References") are cited in large quantities throughout this specification. Each of the cited references is individually incorporated herein by reference for its specific reference.

Finally, it is understood that the embodiments of the invention disclosed herein are intended to illustrate the principles of the invention. Other modifications that may be employed are within the scope of the invention. Thus, for example, but not limited to, alternative configurations of the invention may be utilized in accordance with the teachings herein. Therefore, the invention is not intended to be limited to

Claims (29)

a compound represented by the following formula: Wherein R ⁴ is R ^d , SO ₂ R ^d , C(=O)R ^d , NH C(=O)R ^d , R ^e , OR ^c or CF ₃ , wherein R ^c is H or C ₁ -C ₁₀ hydrocarbyl And R ^d is a substituted heterocyclic ring, an unsubstituted heterocyclic ring or an unsubstituted carbocyclic ring, and R ^e is a substituted heteroaryl group or a substituted phenyl group; and n is 1 or 2. The compound of claim 1, which is represented by the following formula: Wherein R ⁴ is: (i) C(=O)R ^d and R ^d is pyrrolidinyl, (ii) SO ₂ R ^d and R ^d is hexahydropyridyl, (iii) NHC(=O)R ^d And R ^d is phenyl or furyl, (iv) imidazolyl, or (v) thiazolyl. The compound of claim 1, which is represented by the following formula: Wherein X is NH or O. The compound of claim 1, wherein R ⁴ is CF ₃ , OR ^c or a phenyl group substituted with at least one OCH ₃ group. The compound of claim 1, which is represented by the following formula: a compound represented by the following formula: Wherein L is NR ² , O, S, C(=O)N, CR ² R ³ CR ² R ³ , CR ² R ³ NR ² , CR ⁴ =CR ⁴ , CR ² R ³ O, CR ² R ³ S NR ² CR ² R ³ , NR ² C(=O), NS(O) _t , OCR ² R ³ , SCR ² R ³ ; V system (CR ² R ³ ) _u , C(=O)CR ² R ³ , CR ² R ³ O, CR ² R ³ OCR ² R ³ , CR ⁴ =CR ⁴ , C≡C, C(=NR ² ) or C(=O); Q series NR ² , O, S(O _t or bond; t = 0, 1, 2; u = 0 to 3; wherein the dotted line indicates the presence or absence of a bond; R ¹ is R ^a , OR ² or NR ² R ³ ; each R ^{a is} independently H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² and R ³ are each independently R ^a , C(=O)R ^a , SO ₂ R ^a Or R ² and R ³ form an optionally substituted carbocyclic, heterocarbocyclic, aryl or heteroaryl ring; each R ^{4 is} independently R ² , OR ^a , C(=O)R ^a , C (=O)NR ² R ³ , NR ² R ³ , NR ^b (=O)R ^a , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , SO ₂ NR ² R ³ , NCOR ^a , halogen , trihalomethyl, CN, S = O, a nitro group, or two R ⁴ groups optionally form of substituted carbocyclic, heteroaryl carbocyclic, aryl or heteroaryl ring; W is and X are each independently Tied ^{N, NR a, NR 5,} O, S, CR 2 R 4 or CR ^4; R ⁵ based ^{R a, C (= O)} R a, SO 2 R a or absent; Y ^1, Y ^2, Y ³ and Y ⁴ are each independently CR ⁴ or N; and NR ² R ³ may form an optionally substituted heterocyclic or heteroaryl ring including pyrrolidine, hexahydropyridine, morpholine and hexahydropyrazine. The compound of claim 6, which has a structure represented by Formula 1A or 1C Wherein in any of Formula 1A and Formula 1C, R ¹ is R ^a , OR ² or NR ² R ³ ; each R ^{a is} independently H, optionally substituted hydrocarbyl, optionally substituted a heteroaryl group which is optionally substituted; R ² and R ³ are each independently R ^a , C(=O)R ^a or SO ₂ R ^a ; each R ^{4 is} independently R ² , OR ^a , NR ² R ³ , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , NCOR ^a , C(=O)R ^a , CONR ² R ³ , halogen, trihalomethyl, CN, S=O or nitrate a group; V is CR ² R ³ , C(=O), C(=O)CR ² R ³ or C(=N)R ² ; and W is O or S. The compound of claim 6, which has the structure represented by Formula 1B Wherein R ¹ is R ^a , OR ² or NR ² R ³ ; each R ^{a is} independently H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; R ² And R ³ are each independently R ^a , C(=O)R ^a or SO ₂ R ^a ; each R ^{4 is} independently R ² , OR ^a , NR ² R ³ , SR ^a , SOR ^a , SO ₂ R ^a , SO ₂ NHR ^a , NCOR ^a , C(=O)R ^a , CONR ² R ³ , halogen, trihalomethyl, CN, S=O or nitro; R ⁶ H or CH ₃ , V system CR ² R ³ , C(=O), C(=O)CR ² R ³ or C=NR ² ; and W is O or S. The compound of claim 7 or 8, wherein R ⁴ is H; and V is C=O. The compound of any one of claims 7, 8 or 9, wherein R ¹ is optionally substituted phenyl or optionally substituted naphthyl. The compound of any one of claims 6 to 10, wherein W is S and X is N. The compound of any one of claims 6 to 10, wherein W is O and X is N. The compound of any one of claims 6 to 11, which is represented by the following formula: Wherein R ¹ is a phenyl group substituted with at least one halogen, a phenyl group substituted with NR ² R ³ , a phenyl group substituted with SO ₂ NR ² R ³ , CR ² R ³ ORd, an unsubstituted naphthyl group, via O (CR ² R ³ ) _n R ^d , NR ^a (CR ² R ³ ) _n R ^d , NR ^a (CR ² R ³ ) _n NR ² R ³ substituted naphthyl group, including a two-membered ring of a pyridyl group and a phenyl group a structure, or a two-membered ring structure comprising a phenyl group and a dioxolanyl group; each R ^{a is} independently H or an optionally substituted hydrocarbyl group (C ₁ -C ₁₀ ); R ² and R ³ are each independently ^{R a, COR a, (CH} 2) n O or SO ₂ R ^a; each R ⁴ is independently R ^a R ^d line based phenyl or morpholinyl group or R ⁵ based H CH _3; R ⁶ is H or CH Department ₃ ; and wherein n is 1, 2, 3 or 4. The compound of claim 13 is represented by the following formula: The compound of any one of claims 5 to 9 and 11 which is represented by the following formula: Wherein R ¹ is phenyl substituted with at least one halogen, phenyl substituted with NR ² R ³ , phenyl substituted with SO ₂ R ^d , naphthyl optionally substituted by O(CR ² R ³ ) _n R ^d Or unsubstituted naphthyl, each R ^{a is} independently H or optionally substituted C ₁ -C ₁₀ hydrocarbyl; R ² , R ³ and each R ^{4 are} independently R ^a , R ^d as appropriate Substituted phenyl or optionally substituted morpholinyl; R ⁵ is H or CH ₃ ; R ⁶ is H or CH ₃ , and wherein n is 1, 2, 3 or 4. A compound of claim 15 which is represented by the formula: The compound of claim 5, which is represented by the following formula: Wherein R ⁴ is a heteroaryl group which is optionally substituted. The compound of claim 17, which is represented by the following formula: A pharmaceutical composition comprising a compound according to any one of claims 1 to 18. A method of treating a viral infection in an individual comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of claim 19, thereby treating the viral infection in the individual. A method of preventing viral infection in an individual comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of claim 19. The method of claim 20 or claim 21, wherein the viral infection is caused by a virus of one or more of the following families: Arenaviridae, Arterivirus, Astroviridae ( Astroviridae), Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Closteroviridae, Cowpea Mosaic Virus (Comoviridae), Coronaviridae, Cystoviridae, Filoviridae, Flaviviridae, Flexiviridae, Hepatic Deoxyriboruvirus ( Hepadnaviridae), Hepatitis virus, Herpesviridae, Leviviridae, Luteoviridae, Mesoniviridae, Mononegavirale, Mosaic Virus (Mosaic Virus), Nidovirale, Nodaviridae, Orthomyxoviridae, Papillomaviridae, Mucus virus families (Paramyxoviridae), small birnaviridae (Picobirnaviridae), small double RNA viruses, Picornaviridae (Picornaviridae), Potato Y virus family (Potyviridae), Reoviridae family, Retroviridae, Roniviridae, Sequiviridae, Parvovirus ( Tenuivirus), Togaviridae, Tombusviridae, Totiviridae, and Turnipviridae. The method of claim 20 or claim 21, wherein the viral infection is caused by: Alfuy virus, Banzi virus, bovine diarrhea virus, Chikungunya virus, dengue fever Virus (Dengue virus, DNV), hepatitis B virus (HBV), hepatitis C virus (HCV), human cytomegalovirus (hCMV), human immunodeficiency virus (HIV), Ilheus virus, Influenza virus (including poultry and pig isolates), rhinovirus, norovirus, adenovirus, Japanese encephalitis virus, Kokobera virus, Kujing virus Kunjin virus), Kyasanur forest disease virus, louping-ill virus, measles virus, MERS-coronavirus (MERS), interstitial pneumonia virus, mosaic virus One, Murray Valley virus, parainfluenza virus, poliovirus, Powassan virus, respiratory syncytial virus (RSV), Rocio virus ), SARS-coronal Virus (SARS), St. Louis encephalitis virus, tick-borne encephalitis virus, West Nile virus (WNV), Ebola virus, Nipah virus ), Lassa virus, Tacaribe virus, Junin virus or yellow fever virus. A pharmaceutical composition according to claim 19 for use in therapy. A pharmaceutical composition for use in claim 24, wherein the pharmaceutical composition is used as a prophylactic Adjuvant administration of sexual or therapeutic vaccines. A method of modulating an innate immune response in a eukaryotic cell, comprising administering to the cell a compound according to any one of claims 1 to 18. The method of claim 26, wherein the cell line is in vivo. The method of claim 27, wherein the cell line is in vitro. A method of treating a viral infection in an individual comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition having the structure: And wherein the viral infection is caused by the Ebola virus.